@article {1731576,
	title = {Endocrine therapy synergizes with SMAC mimetics to potentiate antigen presentation and tumor regression in hormone receptor-positive breast cancer},
	journal = {Cancer Res},
	year = {2023},
	month = {2023 Jul 14},
	abstract = {Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics analysis of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated B2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC-mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I specific T-cell mediated cytotoxicity. Remarkably, the combination of ET and SMAC-mimetics, which also block pro-survival effects of NF-κB signaling through the degradation of inhibitors of apoptosis (IAP) proteins, elicited tumor regression through cell-autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer.},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-23-1711},
	author = {Hermida-Prado, Francisco and Xie, Yingtian and Sherman, Shira and Nagy, Zsuzsanna and Russo, Douglas and Akhshi, Tara and Chu, Zhengtao and Feit, Avery and Campisi, Marco and Chen, Minyue and Nardone, Agostina and Guarducci, Cristina and Lim, Klothilda and Font-Tello, Alba and Lee, Irene and Garc{\'\i}a-Pedrero, Juana and Canadas, Israel and Agudo, Judith and Huang, Ying and Sella, Tal and Jin, Qingchun and Tayob, Nabihah and Mittendorf, Elizabeth A and Tolaney, Sara M and Qiu, Xintao and Long, Henry and Symmans, William F and Lin, Jia-Ren and Santagata, Sandro and Bedrosian, Isabelle and Yardley, Denise A and Mayer, Ingrid A and Richardson, Edward T and Oliveira, Giacomo and Wu, Catherine J and Schuster, Eugene F and Dowsett, Mitch and Welm, Alana L and Barbie, David and Metzger, Otto and Jeselsohn, Rinath}
}
@article {1731571,
	title = {Impact of supraphysiologic MDM2 expression on chromatin networks and therapeutic responses in sarcoma},
	journal = {Cell Genom},
	volume = {3},
	number = {7},
	year = {2023},
	month = {2023 Jul 12},
	pages = {100321},
	abstract = {Amplification of MDM2 on supernumerary chromosomes is a common mechanism of P53 inactivation across tumors. Here, we investigated the impact of MDM2 overexpression on chromatin, gene expression, and cellular phenotypes in liposarcoma. Three independent regulatory circuits predominate in aggressive, dedifferentiated tumors. RUNX and AP-1 family transcription factors bind mesenchymal gene enhancers. P53 and MDM2 co-occupy enhancers and promoters associated with P53 signaling. When highly expressed, MDM2 also binds thousands of P53-independent growth and stress response genes, whose promoters engage in multi-way topological interactions. Overexpressed MDM2 concentrates within nuclear foci that co-localize with PML and YY1 and could also contribute to P53-independent phenotypes associated with supraphysiologic MDM2. Importantly, we observe striking cell-to-cell variability in MDM2 copy number and expression in tumors and models. Whereas liposarcoma cells are generally sensitive to MDM2 inhibitors and their combination with pro-apoptotic drugs, MDM2-high cells tolerate them and may underlie the poor clinical efficacy of these agents.},
	issn = {2666-979X},
	doi = {10.1016/j.xgen.2023.100321},
	author = {Bevill, Samantha M and Casan{\'\i}-Gald{\'o}n, Salvador and El Farran, Chadi A and Cytrynbaum, Eli G and Macias, Kevin A and Oldeman, Sylvie E and Oliveira, Kayla J and Moore, Molly M and Hegazi, Esmat and Adriaens, Carmen and Najm, Fadi J and Demetri, George D and Cohen, Sonia and Mullen, John T and Riggi, Nicol{\`o} and Johnstone, Sarah E and Bernstein, Bradley E}
}
@article {1731566,
	title = {Modeling epigenetic lesions that cause gliomas},
	journal = {Cell},
	year = {2023},
	month = {2023 Jul 20},
	abstract = {Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in\&nbsp;vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in\&nbsp;vitro and gliomagenesis in\&nbsp;vivo.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2023.06.022},
	author = {Rahme, Gilbert J and Javed, Nauman M and Puorro, Kaitlyn L and Xin, Shouhui and Hovestadt, Volker and Johnstone, Sarah E and Bernstein, Bradley E}
}
@article {1717156,
	title = {Age-associated remodeling of T cell immunity and metabolism},
	journal = {Cell Metab},
	volume = {35},
	number = {1},
	year = {2023},
	month = {2023 Jan 03},
	pages = {36-55},
	abstract = {Aging results in remodeling of T\&nbsp;cell immunity and is associated with poor clinical outcomes in age-related diseases such as cancer. Among the hallmarks of aging, changes in host and cellular metabolism critically affect the development, maintenance, and function of T\&nbsp;cells. Although metabolic perturbations impact anti-tumor T\&nbsp;cell responses, the link between age-associated metabolic dysfunction and anti-tumor immunity remains unclear. In this review, we summarize recent advances in our understanding of aged T\&nbsp;cell metabolism, with a focus on the bioenergetic and immunologic features of T\&nbsp;cell subsets unique to the aging process. We also survey insights into mechanisms of metabolic T\&nbsp;cell dysfunction in aging and discuss the impacts of aging on the efficacy of cancer immunotherapy. As the average life expectancy continues to increase, understanding the interplay between age-related metabolic reprogramming and maladaptive T\&nbsp;cell immunity will be instrumental for the development of therapeutic strategies for older patients.},
	keywords = {Aged, Energy Metabolism, Humans, Immunotherapy, Neoplasms, T-Lymphocyte Subsets, Tumor Microenvironment},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2022.11.005},
	author = {Han, SeongJun and Georgiev, Peter and Ringel, Alison E and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1717066,
	title = {Chemical biology approaches to uncovering nuclear ROS control},
	journal = {Curr Opin Chem Biol},
	volume = {76},
	year = {2023},
	month = {2023 Jun 21},
	pages = {102352},
	abstract = {Heightened concentrations of reactive metabolites, including reactive oxygen species (ROS), can damage all macromolecules leading to the erosion of cellular fidelity. In this regard, the control of ROS in the nuclues is essential for cellular homeostasis, and dysregulation of nuclear ROS has been attributed to multiple pathologies and the mechanism of action of certain chemotherapies. How nuclear ROS is generated, detoxified and sensed is poorly understood, and stems in part, from a historical lack of tools that allow for its precise generation and detection. Here, we summarize the latest advances in chemical biology inspired approaches that have been developed to study nuclear ROS and highlight how these tools have led to major breakthroughs in understanding its regulation. The continued development and application of chemical biology approaches to understand nuclear ROS promises to unlock fundamental insights into human physiology and disease.},
	issn = {1879-0402},
	doi = {10.1016/j.cbpa.2023.102352},
	author = {Zhang, Junbing and Bar-Peled, Liron}
}
@article {1717106,
	title = {Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC},
	journal = {PLoS Biol},
	volume = {21},
	number = {4},
	year = {2023},
	month = {2023 Apr},
	pages = {e3002038},
	abstract = {While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs and cause dramatic tumor regression in aggressive human and mouse CRPC models. Notably, EZH2 and HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation and histone deacetylation, respectively. Accordingly, we show that suppression of both EZH2 and HDAC are required to derepress/induce a subset of EZH2 targets, by promoting the sequential demethylation and acetylation of histone H3. Moreover, we find that the induction of one of these targets, ATF3, which is a broad stress response gene, is critical for the therapeutic response. Importantly, in human tumors, low ATF3 levels are associated with decreased survival. Moreover, EZH2- and ATF3-mediated transcriptional programs inversely correlate and are most highly/lowly expressed in advanced disease. Together, these studies identify a promising therapeutic strategy for CRPC and suggest that these two major epigenetic regulators buffer prostate cancers from a lethal response to cellular stresses, thereby conferring a tractable therapeutic vulnerability.},
	keywords = {Animals, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Histone Deacetylases, Histones, Humans, Male, Mice, Prostatic Neoplasms, Castration-Resistant},
	issn = {1545-7885},
	doi = {10.1371/journal.pbio.3002038},
	author = {Schade, Amy E and Kuzmickas, Ryan and Rodriguez, Carrie L and Mattioli, Kaia and Enos, Miriam and Gardner, Alycia and Cichowski, Karen}
}
@article {1717061,
	title = {Co-targeting a MYC-eIF4A survival axis improves the efficacy of KRAS inhibitors in lung cancer},
	journal = {J Clin Invest},
	year = {2023},
	month = {2023 Jun 29},
	abstract = {Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to co-target RAS and mTOR pathways, however toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identify the most therapeutically important eIF4F-translated targets. Here we show that an eIF4A inhibitor, which targets a component of eIF4F, dramatically enhances the effects of KRAS G12C inhibitors in NSCLCs and together these agents induce potent tumor regression in vivo. By screening a broad panel of eIF4F targets, we show that this cooperativity is driven by effects on BCL-2 family proteins. Moreover, because multiple BCL-2 family members are concomitantly suppressed, these agents are broadly efficacious in NSCLCs, irrespective of their dependency on MCL1, BCL-xL, or BCL-2, which is known to be heterogeneous. Finally, we show that MYC overexpression confers sensitivity to this combination because it creates a dependency on eIF4A for BCL-2 family protein expression. Together, these studies identify a promising therapeutic strategy for KRAS-mutant NSCLCs, demonstrate that BCL-2 proteins are the key mediators of the therapeutic response in this tumor type, and uncover a predictive biomarker of sensitivity.},
	issn = {1558-8238},
	doi = {10.1172/JCI167651},
	author = {Nardi, Francesca and Perurena, Naiara and Schade, Amy E and Li, Ze-Hua and Ngo, Kenneth and Ivanova, Elena V and Saldanha, Aisha and Li, Chendi and Gokhale, Prafulla C and Hata, Aaron N and Barbie, David A and Paweletz, Cloud P and Janne, Pasi A and Cichowski, Karen}
}
@article {1717101,
	title = {A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories},
	journal = {Nat Med},
	volume = {29},
	number = {5},
	year = {2023},
	month = {2023 May},
	pages = {1113-1122},
	abstract = {Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet). For cancer occurrence within 36 months, the performance of the best DNPR model has area under the receiver operating characteristic (AUROC) curve = 0.88 and decreases to AUROC (3m) = 0.83 when disease events within 3 months before cancer diagnosis are excluded from training, with an estimated relative risk of 59 for 1,000 highest-risk patients older than age 50 years. Cross-application of the Danish model to US-VA data had lower performance (AUROC = 0.71), and retraining was needed to improve performance (AUROC = 0.78, AUROC (3m) = 0.76). These results improve the ability to design realistic surveillance programs for patients at elevated risk, potentially benefiting lifespan and quality of life by early detection of this aggressive cancer.},
	keywords = {Algorithms, Artificial Intelligence, Deep Learning, Humans, Middle Aged, Pancreatic Neoplasms, Quality of Life},
	issn = {1546-170X},
	doi = {10.1038/s41591-023-02332-5},
	author = {Placido, Davide and Yuan, Bo and Hjaltelin, Jessica X and Zheng, Chunlei and Haue, Amalie D and Chmura, Piotr J and Yuan, Chen and Kim, Jihye and Umeton, Renato and Antell, Gregory and Chowdhury, Alexander and Franz, Alexandra and Brais, Lauren and Andrews, Elizabeth and Marks, Debora S and Regev, Aviv and Ayandeh, Siamack and Brophy, Mary T and Do, Nhan V and Kraft, Peter and Wolpin, Brian M and Rosenthal, Michael H and Fillmore, Nathanael R and Brunak, S{\o}ren and Sander, Chris}
}
@article {1717076,
	title = {Heritable transcriptional defects from aberrations of nuclear architecture},
	journal = {Nature},
	volume = {619},
	number = {7968},
	year = {2023},
	month = {2023 Jul},
	pages = {184-192},
	abstract = {Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance1-3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.},
	keywords = {Cell Nucleus, Chromatin, Chromosomal Instability, Chromosome Aberrations, Chromosomes, Humans, Neoplasms},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06157-7},
	author = {Papathanasiou, Stamatis and Mynhier, Nikos A and Liu, Shiwei and Brunette, Gregory and Stokasimov, Ema and Jacob, Etai and Li, Lanting and Comenho, Caroline and van Steensel, Bas and Buenrostro, Jason D and Zhang, Cheng-Zhong and Pellman, David}
}
@article {1717071,
	title = {High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers},
	journal = {Nat Cancer},
	year = {2023},
	month = {2023 Jun 22},
	abstract = {Precision medicine is critically dependent on better methods for diagnosing and staging disease and predicting drug response. Histopathology using hematoxylin and eosin (H\&amp;E)-stained tissue (not genomics) remains the primary diagnostic method in cancer. Recently developed highly multiplexed tissue imaging methods promise to enhance research studies and clinical practice with precise, spatially resolved single-cell data. Here, we describe the {\textquoteright}Orion{\textquoteright} platform for collecting H\&amp;E and high-plex immunofluorescence images from the same cells in a whole-slide format suitable for diagnosis. Using a retrospective cohort of 74 colorectal cancer resections, we show that immunofluorescence and H\&amp;E images provide human experts and machine learning algorithms with complementary information that can be used to generate interpretable, multiplexed image-based models predictive of progression-free survival. Combining models of immune infiltration and tumor-intrinsic features achieves a 10- to 20-fold discrimination between rapid and slow (or no) progression, demonstrating the ability of multimodal tissue imaging to generate high-performance biomarkers.},
	issn = {2662-1347},
	doi = {10.1038/s43018-023-00576-1},
	author = {Lin, Jia-Ren and Chen, Yu-An and Campton, Daniel and Cooper, Jeremy and Coy, Shannon and Yapp, Clarence and Tefft, Juliann B and McCarty, Erin and Ligon, Keith L and Rodig, Scott J and Reese, Steven and George, Tad and Santagata, Sandro and Sorger, Peter K}
}
@article {1717151,
	title = {High-throughput, targeted MHC class I immunopeptidomics using a functional genetics screening platform},
	journal = {Nat Biotechnol},
	year = {2023},
	month = {2023 Jan 02},
	abstract = {Identification of CD8+ T cell epitopes is critical for the development of immunotherapeutics. Existing methods for major histocompatibility complex class I (MHC class I) ligand discovery are time intensive, specialized and unable to interrogate specific proteins on a large scale. Here, we present EpiScan, which uses surface MHC class I levels as a readout for whether a genetically encoded peptide is an MHC class I ligand. Predetermined starting pools composed of \&gt;100,000 peptides can be designed using oligonucleotide synthesis, permitting large-scale MHC class I screening. We exploit this programmability of EpiScan to uncover an unappreciated role for cysteine that increases the number of predicted ligands by 9-21\%, reveal affinity hierarchies by analysis of biased anchor peptide libraries and screen viral proteomes for MHC class I ligands. Using these data, we generate and iteratively refine peptide binding predictions to create EpiScan Predictor. EpiScan Predictor performs comparably to other state-of-the-art MHC class I peptide binding prediction algorithms without suffering from underrepresentation of cysteine-containing peptides. Thus, targeted immunopeptidomics using EpiScan will accelerate CD8+ T cell epitope discovery toward the goal of individual-specific immunotherapeutics.},
	issn = {1546-1696},
	doi = {10.1038/s41587-022-01566-x},
	author = {Bruno, Peter M and Timms, Richard T and Abdelfattah, Nouran S and Leng, Yumei and Lelis, Felipe J N and Wesemann, Duane R and Yu, Xu G and Elledge, Stephen J}
}
@article {1717121,
	title = {Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway},
	journal = {bioRxiv},
	year = {2023},
	month = {2023 Mar 11},
	abstract = {Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, it{\textquoteright}s unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H 2 O 2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H 2 O 2 . Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H 2 O 2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.},
	doi = {10.1101/2023.03.11.532189},
	author = {Zhang, Junbing and Simpson, Claire M and Berner, Jacqueline and Chong, Harrison B and Fang, Jiafeng and Sahin, Zehra Ordulu and Weiss-Sadan, Tom and Possemato, Anthony P and Harry, Stefan and Takahashi, Mariko and Yang, Tzu-Yi and Richter, Marianne and Patel, Himani and Smith, Abby E and Carlin, Alexander D and Hubertus de Groot, Adriaan F and Wolf, Konstantin and Shi, Lei and Wei, Ting-Yu and D{\"u}rr, Benedikt R and Chen, Nicholas J and Vornb{\"a}umen, Tristan and Wichmann, Nina O and Pooladanda, Venkatesh and Matoba, Yuske and Kumar, Shaan and Kim, Eugene and Bouberhan, Sara and Olivia, Esther and Rueda, Bo and Bardeesy, Nabeel and Liau, Brian and Lawrence, Michael and Stokes, Matt P and Beausoleil, Sean A and Bar-Peled, Liron}
}
@article {1717116,
	title = {Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma},
	journal = {Cancer Cell},
	volume = {41},
	number = {5},
	year = {2023},
	month = {2023 May 08},
	pages = {871-886.e10},
	abstract = {Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T\&nbsp;cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T\&nbsp;cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1+ PD-1+ progenitor CD8+ T\&nbsp;cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8+ T\&nbsp;cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8+ T\&nbsp;cell anti-tumor responses.},
	keywords = {Adenocarcinoma of Lung, Animals, CD8-Positive T-Lymphocytes, Humans, Immunity, Immunotherapy, Lung Neoplasms, Mice},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2023.03.015},
	author = {Gaglia, Giorgio and Burger, Megan L and Ritch, Cecily C and Rammos, Danae and Dai, Yang and Crossland, Grace E and Tavana, Sara Z and Warchol, Simon and Jaeger, Alex M and Naranjo, Santiago and Coy, Shannon and Nirmal, Ajit J and Krueger, Robert and Lin, Jia-Ren and Hanspeter Pfister and Sorger, Peter K and Jacks, Tyler and Santagata, Sandro}
}
@article {1717141,
	title = {Mechanisms of Resistance to Antibody-Drug Conjugates},
	journal = {Cancers (Basel)},
	volume = {15},
	number = {4},
	year = {2023},
	month = {2023 Feb 17},
	abstract = {Antibody-drug conjugates (ADCs), with antibodies targeted against specific antigens linked to cytotoxic payloads, offer the opportunity for a more specific delivery of chemotherapy and other bioactive payloads to minimize side effects. First approved in the setting of HER2+ breast cancer, more recent ADCs have been developed for triple-negative breast cancer (TNBC) and, most recently, hormone receptor-positive (HR+) breast cancer. While antibody-drug conjugates have compared favorably against traditional chemotherapy in some settings, patients eventually progress on these therapies and require a change in treatment. Mechanisms to explain the resistance to ADCs are highly sought after, in hopes of developing next-line treatment options and expanding the therapeutic windows of existing therapies. These resistance mechanisms are categorized as follows: change in antigen expression, change in ADC processing and resistance, and efflux of the ADC payload. This paper reviews the recently published literature on these mechanisms as well as potential options to overcome these barriers.},
	issn = {2072-6694},
	doi = {10.3390/cancers15041278},
	author = {Abelman, Rachel Occhiogrosso and Wu, Bogang and Spring, Laura M and Ellisen, Leif W and Bardia, Aditya}
}
@article {1717146,
	title = {Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer},
	journal = {Cell},
	volume = {186},
	number = {2},
	year = {2023},
	month = {2023 Jan 19},
	pages = {363-381.e19},
	abstract = {Advanced solid cancers are complex assemblies of tumor, immune, and stromal cells characterized by high intratumoral variation. We use highly multiplexed tissue imaging, 3D reconstruction, spatial statistics, and machine learning to identify cell types and states underlying morphological features of known diagnostic and prognostic significance in colorectal cancer. Quantitation of these features in high-plex marker space reveals recurrent transitions from one tumor morphology to the next, some of which are coincident with long-range gradients in the expression of oncogenes and epigenetic regulators. At the tumor invasive margin, where tumor, normal, and immune cells compete, T\&nbsp;cell suppression involves multiple cell types and 3D imaging shows that seemingly localized 2D features such as tertiary lymphoid structures are commonly interconnected and have graded molecular properties. Thus, while cancer genetics emphasizes the importance of discrete changes in tumor state, whole-specimen imaging reveals large-scale morphological and molecular gradients analogous to those in developing tissues.},
	keywords = {Adenocarcinoma, Colorectal Neoplasms, Humans, Image Processing, Computer-Assisted, Oncogenes, Tumor Microenvironment},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2022.12.028},
	author = {Lin, Jia-Ren and Wang, Shu and Coy, Shannon and Chen, Yu-An and Yapp, Clarence and Tyler, Madison and Nariya, Maulik K and Heiser, Cody N and Lau, Ken S and Santagata, Sandro and Sorger, Peter K}
}
@article {1717126,
	title = {Multi-range ERK responses shape the proliferative trajectory of single cells following oncogene induction},
	journal = {Cell Rep},
	volume = {42},
	number = {3},
	year = {2023},
	month = {2023 Mar 28},
	pages = {112252},
	abstract = {Oncogene-induced senescence is a phenomenon in which aberrant oncogene expression causes non-transformed cells to enter a non-proliferative state. Cells undergoing oncogenic induction display phenotypic heterogeneity, with some cells senescing and others remaining proliferative. The causes of heterogeneity remain unclear. We studied the sources of heterogeneity in the responses of human epithelial cells to oncogenic BRAFV600E expression. We found that a narrow expression range of BRAFV600E generated a wide range of activities of its downstream effector ERK. In population-level and single-cell assays, ERK activity displayed a non-monotonic relationship to proliferation, with intermediate ERK activities leading to maximal proliferation. We profiled gene expression across a range of ERK activities over time and characterized four distinct ERK response classes, which we propose act in concert to generate the ERK-proliferation response. Altogether, our studies map the input-output relationships between ERK activity and proliferation, elucidating how heterogeneity can be generated during oncogene induction.},
	keywords = {Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Humans, Mutation, Oncogenes, Proto-Oncogene Proteins B-raf},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2023.112252},
	author = {Chen, Jia-Yun and Hug, Clemens and Reyes, Jos{\'e} and Tian, Chengzhe and Gerosa, Luca and Fr{\"o}hlich, Fabian and Ponsioen, Bas and Snippert, Hugo J G and Spencer, Sabrina L and Jambhekar, Ashwini and Sorger, Peter K and Lahav, Galit}
}
@article {1717136,
	title = {NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer},
	journal = {Cell Metab},
	volume = {35},
	number = {3},
	year = {2023},
	month = {2023 Mar 07},
	pages = {487-503.e7},
	abstract = {Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in \&gt;13\% of the cell lines-an effect that was~rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.},
	keywords = {Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Humans, Kelch-Like ECH-Associated Protein 1, Lung Neoplasms, NAD, NF-E2-Related Factor 2, Oxidative Stress, Signal Transduction},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2023.01.012},
	author = {Weiss-Sadan, Tommy and Ge, Maolin and Hayashi, Makiko and Gohar, Magdy and Yao, Cong-Hui and de Groot, Adriaan and Harry, Stefan and Carlin, Alexander and Fischer, Hannah and Shi, Lei and Wei, Ting-Yu and Adelmann, Charles H and Wolf, Konstantin and Vornb{\"a}umen, Tristan and D{\"u}rr, Benedikt R and Takahashi, Mariko and Richter, Marianne and Zhang, Junbing and Yang, Tzu-Yi and Vijay, Vindhya and Fisher, David E and Hata, Aaron N and Haigis, Marcia C and Mostoslavsky, Raul and Bardeesy, Nabeel and Papagiannakopoulos, Thales and Bar-Peled, Liron}
}
@article {1717086,
	title = {Pancreatic Neoplasms Are Frighteningly Common: A Role for Immune Surveillance?},
	journal = {Cancer Discov},
	volume = {13},
	number = {6},
	year = {2023},
	month = {2023 Jun 02},
	pages = {1288-1290},
	abstract = {Carpenter and colleagues analyze organ donors to find that pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of pancreatic ductal adenocarcinoma, are highly prevalent in the average healthy adult starting from a young age. Why these precursor lesions do not progress to cancer in most people is a mystery. See related article by Carpenter et al., p. 1324 (1).},
	keywords = {Adult, Carcinoma in Situ, Carcinoma, Pancreatic Ductal, Humans, Pancreas, Pancreatic Neoplasms, Tissue Donors, Transcriptome, Tumor Microenvironment},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-23-0332},
	author = {Hoffman, Megan T and Dougan, Stephanie K}
}
@article {1717131,
	title = {Polymerase θ inhibition activates the cGAS-STING pathway and cooperates with immune checkpoint blockade in models of BRCA-deficient cancer},
	journal = {Nat Commun},
	volume = {14},
	number = {1},
	year = {2023},
	month = {2023 Mar 13},
	pages = {1390},
	abstract = {Recently developed inhibitors of polymerase theta (POLθ) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POLθ inhibition in immunocompetent models of BRCA1-deficient triple-negative breast cancer (TNBC) or BRCA2-deficient pancreatic ductal adenocarcinoma (PDAC). We demonstrate that genetic POLQ depletion or pharmacological POLθ inhibition induces both innate and adaptive immune responses in these models. POLθ inhibition resulted in increased micronuclei, cGAS/STING pathway activation, type I interferon gene expression, CD8+ T cell infiltration and activation, local paracrine activation of dendritic cells and upregulation of PD-L1 expression. Depletion of CD8+ T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.},
	keywords = {Carcinoma, Pancreatic Ductal, CD8-Positive T-Lymphocytes, DNA-Directed DNA Polymerase, Humans, Immune Checkpoint Inhibitors, Pancreatic Neoplasms, Tumor Microenvironment},
	issn = {2041-1723},
	doi = {10.1038/s41467-023-37096-6},
	author = {Patterson-Fortin, Jeffrey and Jadhav, Heta and Pantelidou, Constantia and Phan, Tin and Grochala, Carter and Mehta, Anita K and Guerriero, Jennifer L and Wulf, Gerburg M and Wolpin, Brian M and Stanger, Ben Z and Aguirre, Andrew J and Cleary, James M and D{\textquoteright}Andrea, Alan D and Shapiro, Geoffrey I}
}
@article {1717096,
	title = {Systematic identification of anticancer drug targets reveals a nucleus-to-mitochondria ROS-sensing pathway},
	journal = {Cell},
	volume = {186},
	number = {11},
	year = {2023},
	month = {2023 May 25},
	pages = {2361-2379.e25},
	abstract = {Multiple anticancer drugs have been proposed to cause cell death, in part, by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs, exactly how the resultant ROS function and are sensed is poorly understood. It remains unclear which proteins the ROS modify and their roles in drug sensitivity/resistance. To answer these questions, we examined 11 anticancer drugs with an integrated proteogenomic approach identifying not only many unique targets but also shared ones-including ribosomal components, suggesting common mechanisms by which drugs regulate translation. We focus on CHK1 that we find is a nuclear H2O2 sensor that launches a cellular program to dampen ROS. CHK1 phosphorylates the mitochondrial DNA-binding protein SSBP1 to prevent its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS-sensing pathway-required to resolve nuclear H2O2 accumulation and mediate resistance to platinum-based agents in ovarian cancers.},
	keywords = {Antineoplastic Agents, Cell Nucleus, Humans, Hydrogen Peroxide, Mitochondria, Reactive Oxygen Species},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2023.04.026},
	author = {Zhang, Junbing and Simpson, Claire M and Berner, Jacqueline and Chong, Harrison B and Fang, Jiafeng and Ordulu, Zehra and Weiss-Sadan, Tommy and Possemato, Anthony P and Harry, Stefan and Takahashi, Mariko and Yang, Tzu-Yi and Richter, Marianne and Patel, Himani and Smith, Abby E and Carlin, Alexander D and Hubertus de Groot, Adriaan F and Wolf, Konstantin and Shi, Lei and Wei, Ting-Yu and D{\"u}rr, Benedikt R and Chen, Nicholas J and Vornb{\"a}umen, Tristan and Wichmann, Nina O and Mahamdeh, Mohammed S and Pooladanda, Venkatesh and Matoba, Yusuke and Kumar, Shaan and Kim, Eugene and Bouberhan, Sara and Oliva, Esther and Rueda, Bo R and Soberman, Roy J and Bardeesy, Nabeel and Liau, Brian B and Lawrence, Michael and Stokes, Matt P and Beausoleil, Sean A and Bar-Peled, Liron}
}
@article {1717161,
	title = {Targeting replication stress in cancer therapy},
	journal = {Nat Rev Drug Discov},
	volume = {22},
	number = {1},
	year = {2023},
	month = {2023 Jan},
	pages = {38-58},
	abstract = {Replication stress is a major cause of genomic instability and a crucial vulnerability of cancer cells. This vulnerability can be therapeutically targeted by inhibiting kinases that coordinate the DNA damage response with cell cycle control, including ATR, CHK1, WEE1 and MYT1 checkpoint kinases. In addition, inhibiting the DNA damage response releases DNA fragments into the cytoplasm, eliciting an innate immune response. Therefore, several ATR, CHK1, WEE1 and MYT1 inhibitors are undergoing clinical evaluation as monotherapies or in combination with chemotherapy, poly[ADP-ribose]polymerase (PARP) inhibitors, or immune checkpoint inhibitors to capitalize on high replication stress, overcome therapeutic resistance and promote effective antitumour immunity. Here, we review current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation.},
	keywords = {Cell Cycle Proteins, Checkpoint Kinase 1, DNA Damage, DNA Replication, Humans, Neoplasms},
	issn = {1474-1784},
	doi = {10.1038/s41573-022-00558-5},
	author = {da Costa, Alexandre Andr{\'e} B A and Chowdhury, Dipanjan and Shapiro, Geoffrey I and D{\textquoteright}Andrea, Alan D and Konstantinopoulos, Panagiotis A}
}
@article {1717056,
	title = {Therapy-induced APOBEC3A drives evolution of persistent cancer cells},
	journal = {Nature},
	year = {2023},
	month = {2023 Jul 05},
	abstract = {Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06303-1},
	author = {Isozaki, Hideko and Sakhtemani, Ramin and Abbasi, Ammal and Nikpour, Naveed and Stanzione, Marcello and Oh, Sunwoo and Langenbucher, Adam and Monroe, Susanna and Su, Wenjia and Cabanos, Heidie Frisco and Siddiqui, Faria M and Phan, Nicole and Jalili, P{\'e}gah and Timonina, Daria and Bilton, Samantha and Gomez-Caraballo, Maria and Archibald, Hannah L and Nangia, Varuna and Dionne, Kristin and Riley, Amanda and Lawlor, Matthew and Banwait, Mandeep Kaur and Cobb, Rosemary G and Zou, Lee and Dyson, Nicholas J and Ott, Christopher J and Benes, Cyril and Getz, Gad and Chan, Chang S and Shaw, Alice T and Gainor, Justin F and Lin, Jessica J and Sequist, Lecia V and Piotrowska, Zofia and Yeap, Beow Y and Engelman, Jeffrey A and Lee, Jake June-Koo and Maruvka, Yosef E and Buisson, R{\'e}mi and Lawrence, Michael S and Hata, Aaron N}
}
@article {1717091,
	title = {Transforming Growth Factor-β Blockade in Pancreatic Cancer Enhances Sensitivity to Combination Chemotherapy},
	journal = {Gastroenterology},
	year = {2023},
	month = {2023 May 30},
	abstract = {BACKGROUND \&amp; AIMS: Transforming growth factor-β (TGFβ) plays pleiotropic roles in pancreatic cancer, including promoting metastasis, attenuating cluster of differentiation 8 (CD8) T-cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFβ inhibition has shown limited efficacy against pancreatic cancer in mice or humans. METHODS: We evaluated the TGFβ-blocking antibody NIS793 in combination with gemcitabine/nanoparticle (albumin-bound)-paclitaxel or FOLFIRINOX (folinic acid [FOL], 5-fluorouracil [F], irinotecan [IRI] and oxaliplatin [OX]) in orthotopic pancreatic cancer models. Single-cell RNA sequencing and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment. RESULTS: Blockade of TGFβ with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, because response to TGFβ blockade was preserved in CD8-depleted or recombination activating gene 2-/- mice. TGFβ blockade decreased total α-smooth muscle actin-positive fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA sequencing on tumor cells sorted ex\&nbsp;vivo revealed that tumor cells treated with TGFβ blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFβ blockade increased chemotherapy-induced cell death in\&nbsp;vivo. CONCLUSIONS: TGFβ regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFβ blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with FOLFIRINOX or gemcitabine/nanoparticle (albumin-bound) paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.},
	issn = {1528-0012},
	doi = {10.1053/j.gastro.2023.05.038},
	author = {Qiang, Li and Hoffman, Megan T and Ali, Lestat R and Castillo, Jaime I and Kageler, Lauren and Temesgen, Ayantu and Lenehan, Patrick and Wang, S Jennifer and Bello, Elisa and Cardot-Ruffino, Victoire and Uribe, Giselle A and Yang, Annan and Dougan, Michael and Aguirre, Andrew J and Raghavan, Srivatsan and Pelletier, Marc and Cremasco, Viviana and Dougan, Stephanie K}
}
@article {1717081,
	title = {Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin},
	journal = {Nature},
	volume = {618},
	number = {7966},
	year = {2023},
	month = {2023 Jun},
	pages = {834-841},
	abstract = {Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues1-4. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin5. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent\&nbsp;tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.},
	keywords = {Bone Marrow Cells, Cell Death, Cell Lineage, Cell Transformation, Neoplastic, Clone Cells, Dendritic Cells, Humans, Leukemia, Myeloid, Acute, Mutation, Organ Specificity, Single-Cell Gene Expression Analysis, Skin, Skin Neoplasms, Ultraviolet Rays},
	issn = {1476-4687},
	doi = {10.1038/s41586-023-06156-8},
	author = {Griffin, Gabriel K and Booth, Christopher A G and Togami, Katsuhiro and Chung, Sun Sook and Ssozi, Daniel and Verga, Julia A and Bouyssou, Juliette M and Lee, Yoke Seng and Shanmugam, Vignesh and Hornick, Jason L and LeBoeuf, Nicole R and Morgan, Elizabeth A and Bernstein, Bradley E and Hovestadt, Volker and van Galen, Peter and Lane, Andrew A}
}
@article {1717111,
	title = {Uncoupled glycerol-3-phosphate shuttle in kidney cancer reveals that cytosolic GPD is essential to support lipid synthesis},
	journal = {Mol Cell},
	volume = {83},
	number = {8},
	year = {2023},
	month = {2023 Apr 20},
	pages = {1340-1349.e7},
	abstract = {The glycerol-3-phosphate shuttle (G3PS) is a major NADH shuttle that regenerates reducing equivalents in the cytosol and produces energy in the mitochondria. Here, we demonstrate that G3PS is uncoupled in kidney cancer cells where the cytosolic reaction is \~{}4.5 times faster than the mitochondrial reaction. The high flux through cytosolic glycerol-3-phosphate dehydrogenase (GPD) is required to maintain redox balance and support lipid synthesis. Interestingly, inhibition of G3PS by knocking down mitochondrial GPD (GPD2) has no effect on mitochondrial respiration. Instead, loss of GPD2 upregulates cytosolic GPD on a transcriptional level and promotes cancer cell proliferation by increasing glycerol-3-phosphate supply. The proliferative advantage of GPD2 knockdown tumor can be abolished by pharmacologic inhibition of lipid synthesis. Taken together, our results suggest that G3PS is not required to run as an intact NADH shuttle but is instead truncated to support complex lipid synthesis in kidney cancer.},
	keywords = {Glycerol, Glycerol-3-Phosphate Dehydrogenase (NAD+), Glycerolphosphate Dehydrogenase, Humans, Kidney Neoplasms, Lipids, NAD, Oxidation-Reduction, Phosphates},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2023.03.023},
	author = {Yao, Cong-Hui and Park, Joon Seok and Kurmi, Kiran and Hu, Song-Hua and Notarangelo, Giulia and Crowley, Joseph and Jacobson, Heidi and Sheng Hui and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1717171,
	title = {Breast cancer prevention by short-term inhibition of TGFβ signaling},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 Dec 07},
	pages = {7558},
	abstract = {Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.},
	keywords = {Animals, Humans, Neoplasms, Rats, Rats, Inbred ACI, Rats, Sprague-Dawley},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-35043-5},
	author = {Ale{\v c}kovi{\'c}, Ma{\v s}a and Cristea, Simona and Gil Del Alcazar, Carlos R and Yan, Pengze and Ding, Lina and Krop, Ethan D and Harper, Nicholas W and Rojas Jimenez, Ernesto and Lu, Donghao and Gulvady, Anushree C and Foidart, Pierre and Seehawer, Marco and Diciaccio, Benedetto and Murphy, Katherine C and Pyrdol, Jason and Anand, Jayati and Garza, Kodie and Wucherpfennig, Kai W and Tamimi, Rulla M and Michor, Franziska and Polyak, Kornelia}
}
@article {1717176,
	title = {CCAR2 functions downstream of the Shieldin complex to promote double-strand break end-joining},
	journal = {Proc Natl Acad Sci U S A},
	volume = {119},
	number = {49},
	year = {2022},
	month = {2022 Dec 06},
	pages = {e2214935119},
	abstract = {The 53BP1-RIF1 pathway restricts the resection of DNA double-strand breaks (DSBs) and promotes blunt end-ligation by non-homologous end joining (NHEJ) repair. The Shieldin complex is a downstream effector of the 53BP1-RIF1 pathway. Here, we identify a component of this pathway, CCAR2/DBC1, which is also required for restriction of DNA end-resection. CCAR2 co-immunoprecipitates with the Shieldin complex, and knockout of CCAR2 in a BRCA1-deficient cell line results in elevated DSB end-resection, RAD51 loading, and PARP inhibitor (PARPi) resistance. Knockout of CCAR2 is epistatic with knockout of other Shieldin proteins. The S1-like RNA-binding domain of CCAR2 is required for its interaction with the Shieldin complex and for suppression of DSB end-resection. CCAR2 functions downstream of the Shieldin complex, and CCAR2 knockout cells have delayed resolution of Shieldin complex foci. Forkhead-associated (FHA)-dependent targeting of CCAR2 to DSB sites re-sensitized BRCA1-/-SHLD2-/- cells to PARPi. Taken together, CCAR2 is a functional component of the 53BP1-RIF1 pathway, promotes the refill of resected DSBs, and suppresses homologous recombination.},
	keywords = {DNA, DNA Breaks, Double-Stranded, DNA End-Joining Repair, Homologous Recombination, Poly(ADP-ribose) Polymerase Inhibitors},
	issn = {1091-6490},
	doi = {10.1073/pnas.2214935119},
	author = {Iyer, Divya Ramalingam and Harada, Naoya and Clairmont, Connor and Jiang, Lige and Martignetti, David and Nguyen, Huy and He, Yizhou Joseph and Chowdhury, Dipanjan and D{\textquoteright}Andrea, Alan D}
}
@article {1717206,
	title = {Correction to: MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state},
	journal = {Cancer Gene Ther},
	volume = {29},
	number = {12},
	year = {2022},
	month = {2022 Dec},
	pages = {2013},
	issn = {1476-5500},
	doi = {10.1038/s41417-022-00523-9},
	author = {Zhang, Wen Cai and Skiados, Nicholas and Aftab, Fareesa and Moreno, Cerena and Silva, Luis and Corbilla, Paul Joshua Anthony and Asara, John M and Hata, Aaron N and Slack, Frank J}
}
@article {1717191,
	title = {Loss of p53 and genetic evolution in pancreatic cancer: Ordered chaos after the guardian is gone},
	journal = {Cancer Cell},
	volume = {40},
	number = {11},
	year = {2022},
	month = {2022 Nov 14},
	pages = {1276-1278},
	abstract = {A recent Nature study delineates a stepwise genomic evolution during pancreatic cancer development, employing an engineered mutant Kras and heterozygous Trp53 mouse model that identifies cells undergoing Trp53 loss of heterozygosity (LOH). Genetic progression post-Trp53 LOH involves clonal deletions, then genome doubling and subsequent accumulation of subclonal gains and amplifications.},
	keywords = {Animals, Evolution, Molecular, Loss of Heterozygosity, Mice, Pancreatic Neoplasms, Tumor Suppressor Protein p53},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2022.10.020},
	author = {Wu, Bogang and Ellisen, Leif W}
}
@article {1717196,
	title = {Multiplexed and reproducible high content screening of live and fixed cells using Dye Drop},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 Nov 14},
	pages = {6918},
	abstract = {High-throughput measurement of cells perturbed using libraries of small molecules, gene knockouts, or different microenvironmental factors is a key step in functional genomics and pre-clinical drug discovery. However, it remains difficult to perform accurate single-cell assays in 384-well plates, limiting many studies to well-average measurements (e.g., CellTiter-Glo{\textregistered}). Here we describe a public domain Dye Drop method that uses sequential density displacement and microscopy to perform multi-step assays on living cells. We use Dye Drop cell viability and DNA replication assays followed by immunofluorescence imaging to collect single-cell dose-response data for 67 investigational and clinical-grade small molecules in 58 breast cancer cell lines. By separating the cytostatic and cytotoxic effects of drugs computationally, we uncover unexpected relationships between the two. Dye Drop is rapid, reproducible, customizable, and compatible with manual or automated laboratory equipment. Dye Drop improves the tradeoff between data content and cost, enabling the collection of information-rich perturbagen-response datasets.},
	keywords = {Antineoplastic Agents, Cell Survival, Drug Discovery, High-Throughput Screening Assays, Microscopy, Staining and Labeling},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-34536-7},
	author = {Mills, Caitlin E and Subramanian, Kartik and Hafner, Marc and Niepel, Mario and Gerosa, Luca and Chung, Mirra and Victor, Chiara and Gaudio, Benjamin and Yapp, Clarence and Nirmal, Ajit J and Clark, Nicholas and Sorger, Peter K}
}
@article {1717201,
	title = {Protocol to isolate live single cells while retaining spatial information by combining cell photolabeling and FACS},
	journal = {STAR Protoc},
	volume = {3},
	number = {4},
	year = {2022},
	month = {2022 Dec 16},
	pages = {101795},
	abstract = {Single-cell techniques have revolutionized biology; however, the required sample processing inherently implies the loss of spatial localization. Here, using an approach called photoconversion of areas to dissect micro-environments (PADME), we detail steps to isolate live single cells from a primary breast tumor while retaining spatial information by combining cell photolabeling and FACS (fluorescence-activated cell sorting). These live cells can be subsequently used for myriad techniques, from flow cytometry to single-cell RNA sequencing or other single cell "omics" approach. For complete details on the use and execution of this protocol, please refer to Baldominos et~al. (2022).},
	keywords = {Flow Cytometry},
	issn = {2666-1667},
	doi = {10.1016/j.xpro.2022.101795},
	author = {Baldominos, Pilar and Barreiro, Olga and von Andrian, Ulrich and Sirera, Rafael and Montero-Llopis, Paula and Agudo, Judith}
}
@article {1717181,
	title = {Spatial intra-tumor heterogeneity is associated with survival of lung adenocarcinoma patients},
	journal = {Cell Genom},
	volume = {2},
	number = {8},
	year = {2022},
	month = {2022 Aug 10},
	abstract = {Intra-tumor heterogeneity (ITH) of human tumors is important for tumor progression, treatment response, and drug resistance. However, the spatial distribution of ITH remains incompletely understood. Here, we present spatial analysis of ITH in lung adenocarcinomas from 147 patients using multi-region mass spectrometry of \&gt;5,000 regions, single-cell copy number sequencing of ~2,000 single cells, and cyclic immunofluorescence of \&gt;10 million cells. We identified two distinct spatial patterns among tumors, termed clustered and random geographic diversification (GD). These patterns were observed in the same samples using both proteomic and genomic data. The random proteomic GD pattern, which is characterized by decreased cell adhesion and lower levels of tumor-interacting endothelial cells, was significantly associated with increased risk of recurrence or death in two independent patient cohorts. Our study presents comprehensive spatial mapping of ITH in lung adenocarcinoma and provides insights into the mechanisms and clinical consequences of GD.},
	issn = {2666-979X},
	doi = {10.1016/j.xgen.2022.100165},
	author = {Wu, Hua-Jun and Temko, Daniel and Maliga, Zoltan and Moreira, Andre L and Sei, Emi and Minussi, Darlan Conterno and Dean, Jamie and Lee, Charlotte and Xu, Qiong and Hochart, Guillaume and Jacobson, Connor A and Yapp, Clarence and Schapiro, Denis and Sorger, Peter K and Seeley, Erin H and Navin, Nicholas and Downey, Robert J and Michor, Franziska}
}
@article {1717211,
	title = {Stitching and registering highly multiplexed whole-slide images of tissues and tumors using ASHLAR},
	journal = {Bioinformatics},
	volume = {38},
	number = {19},
	year = {2022},
	month = {2022 Sep 30},
	pages = {4613-4621},
	abstract = {MOTIVATION: Stitching microscope images into a mosaic is an essential step in the analysis and visualization of large biological specimens, particularly human and animal tissues. Recent approaches to highly multiplexed imaging generate high-plex data from sequential rounds of lower-plex imaging. These multiplexed imaging methods promise to yield precise molecular single-cell data and information on cellular neighborhoods and tissue architecture. However, attaining mosaic images with single-cell accuracy requires robust image stitching and image registration capabilities that are not met by existing methods.

RESULTS: We describe the development and testing of ASHLAR, a Python tool for coordinated stitching and registration of 103 or more individual multiplexed images to generate accurate whole-slide mosaics. ASHLAR reads image formats from most commercial microscopes and slide scanners, and we show that it performs better than existing open-source and commercial software. ASHLAR outputs standard OME-TIFF images that are ready for analysis by other open-source tools and recently developed image analysis pipelines.

AVAILABILITY AND IMPLEMENTATION: ASHLAR is written in Python and is available under the MIT license at https://github.com/labsyspharm/ashlar. The newly published data underlying this article are available in Sage Synapse at https://dx.doi.org/10.7303/syn25826362; the availability of other previously published data re-analyzed in this article is described in Supplementary Table S4. An informational website with user guides and test data is available at https://labsyspharm.github.io/ashlar/.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},
	keywords = {Animals, Data Collection, Humans, Image Processing, Computer-Assisted, Microscopy, Neoplasms, Software},
	issn = {1367-4811},
	doi = {10.1093/bioinformatics/btac544},
	author = {Muhlich, Jeremy L and Chen, Yu-An and Yapp, Clarence and Russell, Douglas and Santagata, Sandro and Sorger, Peter K}
}
@article {1717186,
	title = {UnMICST: Deep learning with real augmentation for robust segmentation of highly multiplexed images of human tissues},
	journal = {Commun Biol},
	volume = {5},
	number = {1},
	year = {2022},
	month = {2022 Nov 18},
	pages = {1263},
	abstract = {Upcoming technologies enable routine collection of highly multiplexed (20-60 channel), subcellular resolution images of mammalian tissues for research and diagnosis. Extracting single cell data from such images requires accurate image segmentation, a challenging problem commonly tackled with deep learning. In this paper, we report two findings that substantially improve image segmentation of tissues using a range of machine learning architectures. First, we unexpectedly find that the inclusion of intentionally defocused and saturated images in training data substantially improves subsequent image segmentation. Such real augmentation outperforms computational augmentation (Gaussian blurring). In addition, we find that it is practical to image the nuclear envelope in multiple tissues using an antibody cocktail thereby better identifying nuclear outlines and improving segmentation. The two approaches cumulatively and substantially improve segmentation on a wide range of tissue types. We speculate that the use of real augmentations will have applications in image processing outside of microscopy.},
	keywords = {Animals, Cell Nucleus, Deep Learning, Humans, Image Processing, Computer-Assisted, machine learning, Mammals},
	issn = {2399-3642},
	doi = {10.1038/s42003-022-04076-3},
	author = {Yapp, Clarence and Novikov, Edward and Jang, Won-Dong and Vallius, Tuulia and Chen, Yu-An and Cicconet, Marcelo and Maliga, Zoltan and Jacobson, Connor A and Wei, Donglai and Santagata, Sandro and Hanspeter Pfister and Sorger, Peter K}
}
@article {1717216,
	title = {Untangling the web of intratumour heterogeneity},
	journal = {Nat Cell Biol},
	volume = {24},
	number = {8},
	year = {2022},
	month = {2022 Aug},
	pages = {1192-1201},
	abstract = {Intratumour heterogeneity (ITH) is a hallmark of cancer that drives tumour evolution and disease progression. Technological and computational advances have enabled us to assess ITH at unprecedented depths, yet this accumulating knowledge has not had a substantial clinical impact. This is in part due to a limited understanding of the functional relevance of ITH and the inadequacy of preclinical experimental models to reproduce it. Here, we discuss progress made in these areas and illuminate future directions.},
	keywords = {Humans, Neoplasms},
	issn = {1476-4679},
	doi = {10.1038/s41556-022-00969-x},
	author = {Li, Zheqi and Seehawer, Marco and Polyak, Kornelia}
}
@article {1656923,
	title = {MET-Induced CD73 Restrains STING-Mediated Immunogenicity of EGFR-Mutant Lung Cancer},
	journal = {Cancer Res},
	volume = {82},
	number = {21},
	year = {2022},
	month = {2022 11 02},
	pages = {4079-4092},
	abstract = {Immunotherapy has shown limited efficacy in patients with EGFR-mutated lung cancer. Efforts to enhance the immunogenicity of EGFR-mutated lung cancer have been unsuccessful to date. Here, we discover that MET amplification, the most common mechanism of resistance to third-generation EGFR tyrosine kinase inhibitors (TKI), activates tumor cell STING, an emerging determinant of cancer immunogenicity (1). However, STING activation was restrained by ectonucleosidase CD73, which is induced in MET-amplified, EGFR-TKI-resistant cells. Systematic genomic analyses and cell line studies confirmed upregulation of CD73 in MET-amplified and MET-activated lung cancer contexts, which depends on coinduction of FOSL1. Pemetrexed (PEM), which is commonly used following EGFR-TKI treatment failure, was identified as an effective potentiator of STING-dependent TBK1-IRF3-STAT1 signaling in MET-amplified, EGFR-TKI-resistant cells. However, PEM treatment also induced adenosine production, which inhibited T-cell responsiveness. In an allogenic humanized mouse model, CD73 deletion enhanced immunogenicity of MET-amplified, EGFR-TKI-resistant cells, and PEM treatment promoted robust responses regardless of CD73 status. Using a physiologic antigen recognition model, inactivation of CD73 significantly increased antigen-specific CD8+ T-cell immunogenicity following PEM treatment. These data reveal that combined PEM and CD73 inhibition can co-opt tumor cell STING induction in TKI-resistant EGFR-mutated lung cancers and promote immunogenicity.

SIGNIFICANCE: MET amplification upregulates CD73 to suppress tumor cell STING induction and T-cell responsiveness in TKI-resistant, EGFR-mutated lung cancer, identifying a strategy to enhance immunogenicity and improve treatment.},
	keywords = {5{\textquoteright}-Nucleotidase, Animals, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Resistance, Neoplasm, ErbB Receptors, Gene Amplification, Lung Neoplasms, Mice, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-22-0770},
	author = {Yoshida, Ryohei and Saigi, Maria and Tani, Tetsuo and Springer, Benjamin F and Shibata, Hirofumi and Kitajima, Shunsuke and Mahadevan, Navin R and Campisi, Marco and Kim, William and Kobayashi, Yoshihisa and Thai, Tran C and Haratani, Koji and Yamamoto, Yurie and Sundararaman, Shriram K and Knelson, Erik H and Vajdi, Amir and Canadas, Israel and Uppaluri, Ravindra and Paweletz, Cloud P and Miret, Juan J and Lizotte, Patrick H and Gokhale, Prafulla C and J{\"a}nne, Pasi A and Barbie, David A}
}
@article {1656926,
	title = {MicroRNA-21 guide and passenger strand regulation of adenylosuccinate lyase-mediated purine metabolism promotes transition to an EGFR-TKI-tolerant persister state},
	journal = {Cancer Gene Ther},
	year = {2022},
	month = {2022 Jul 15},
	abstract = {In EGFR-mutant lung cancer, drug-tolerant persister cells (DTPCs) show prolonged survival when receiving EGFR tyrosine kinase inhibitor (TKI) treatments. They are a likely source of drug resistance, but little is known about how these cells tolerate drugs. Ribonucleic acids (RNAs) molecules control cell growth and stress responses. Nucleic acid metabolism provides metabolites, such as purines, supporting RNA synthesis and downstream functions. Recently, noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), have received attention due to their capacity to repress gene expression via inhibitory binding to downstream messenger RNAs (mRNAs). Here, our study links miRNA expression to purine metabolism and drug tolerance. MiR-21-5p (guide strand) is a commonly upregulated miRNA in disease states, including cancer and drug resistance. However, the expression and function of miR-21-3p (passenger strand) are not well understood. We found that upregulation of miR-21-5p and miR-21-3p tune purine metabolism leading to increased drug tolerance. Metabolomics data demonstrated that purine metabolism was the top pathway in the DTPCs compared with the parental cells. The changes in purine metabolites in the DTPCs were partially rescued by targeting miR-21. Analysis of protein levels in the DTPCs showed that reduced expression of adenylosuccinate lyase (ADSL) was reversed after the miR-21 knockdown. ADSL is an essential enzyme in the de novo purine biosynthesis pathway by converting succino-5-aminoimidazole-4-carboxamide riboside (succino-AICAR or SAICAR) to AICAR (or acadesine) as well as adenylosuccinate to adenosine monophosphate (AMP). In the DTPCs, miR-21-5p and miR-21-3p repress ADSL expression. The levels of top decreased metabolite in the DTPCs, AICAR was reversed when miR-21 was blocked. AICAR induced oxidative stress, evidenced by increased reactive oxygen species (ROS) and reduced expression of nuclear factor erythroid-2-related factor 2 (NRF2). Concurrently, miR-21 knockdown induced ROS generation. Therapeutically, a combination of AICAR and osimertinib increased ROS levels and decreased osimertinib-induced NRF2 expression. In a MIR21 knockout mouse model, MIR21 loss-of-function led to increased purine metabolites but reduced ROS scavenging capacity in lung tissues in physiological conditions. Our data has established a link between ncRNAs, purine metabolism, and the redox imbalance pathway. This discovery will increase knowledge of the complexity of the regulatory RNA network and potentially enable novel therapeutic options for drug-resistant patients.},
	issn = {1476-5500},
	doi = {10.1038/s41417-022-00504-y},
	author = {Zhang, Wen Cai and Skiados, Nicholas and Aftab, Fareesa and Moreno, Cerena and Silva, Luis and Corbilla, Paul Joshua Anthony and Asara, John M and Hata, Aaron N and Slack, Frank J}
}
@article {1656921,
	title = {MPS1 inhibition primes immunogenicity of KRAS-LKB1 mutant lung cancer},
	journal = {Cancer Cell},
	volume = {40},
	number = {10},
	year = {2022},
	month = {2022 Oct 10},
	pages = {1128-1144.e8},
	abstract = {KRAS-LKB1 (KL) mutant lung cancers silence STING owing to intrinsic mitochondrial dysfunction, resulting in T\&nbsp;cell exclusion and resistance to programmed cell death (ligand) 1 (PD-[L]1) blockade. Here we discover that KL cells also minimize intracellular accumulation of 2{\textquoteright}3{\textquoteright}-cyclic GMP-AMP (2{\textquoteright}3{\textquoteright}-cGAMP) to further avoid downstream STING and STAT1 activation. An unbiased screen to co-opt this vulnerability reveals that transient MPS1 inhibition (MPS1i) potently re-engages this pathway in KL cells via micronuclei generation. This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T\&nbsp;cell infiltration in\&nbsp;vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.},
	keywords = {Decitabine, Genes, ras, Humans, Ligands, Lung Neoplasms, Proto-Oncogene Proteins p21(ras)},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2022.08.015},
	author = {Kitajima, Shunsuke and Tani, Tetsuo and Springer, Benjamin F and Campisi, Marco and Osaki, Tatsuya and Haratani, Koji and Chen, Minyue and Knelson, Erik H and Mahadevan, Navin R and Ritter, Jessica and Yoshida, Ryohei and K{\"o}hler, Jens and Ogino, Atsuko and Nozawa, Ryu-Suke and Sundararaman, Shriram K and Thai, Tran C and Homme, Mizuki and Piel, Brandon and Kivlehan, Sophie and Obua, Bonje N and Purcell, Connor and Yajima, Mamiko and Barbie, Thanh U and Lizotte, Patrick H and J{\"a}nne, Pasi A and Paweletz, Cloud P and Gokhale, Prafulla C and Barbie, David A}
}
@article {1656920,
	title = {Oncometabolite d-2HG alters T cell metabolism to impair CD8 T cell function},
	journal = {Science},
	volume = {377},
	number = {6614},
	year = {2022},
	month = {2022 09 30},
	pages = {1519-1529},
	abstract = {Gain-of-function mutations in isocitrate dehydrogenase (IDH) in human cancers result in the production of d-2-hydroxyglutarate (d-2HG), an oncometabolite that promotes tumorigenesis through epigenetic alterations. The cancer cell-intrinsic effects of d-2HG are well understood, but its tumor cell-nonautonomous roles remain poorly explored. We compared the oncometabolite d-2HG with its enantiomer, l-2HG, and found that tumor-derived d-2HG was taken up by CD8+ T cells and altered their metabolism and antitumor functions in an acute and reversible fashion. We identified the glycolytic enzyme lactate dehydrogenase (LDH) as a molecular target of d-2HG. d-2HG and inhibition of LDH drive a metabolic program and immune CD8+ T cell signature marked by decreased cytotoxicity and impaired interferon-γ signaling that was recapitulated in clinical samples from human patients with IDH1 mutant gliomas.},
	keywords = {Animals, Carcinogenesis, CD8-Positive T-Lymphocytes, Gain of Function Mutation, Glutarates, Humans, Interferon-gamma, Isocitrate Dehydrogenase, L-Lactate Dehydrogenase, Mice, Neoplasms},
	issn = {1095-9203},
	doi = {10.1126/science.abj5104},
	author = {Notarangelo, Giulia and Spinelli, Jessica B and Perez, Elizabeth M and Baker, Gregory J and Kurmi, Kiran and Elia, Ilaria and Stopka, Sylwia A and Baquer, Gerard and Lin, Jia-Ren and Golby, Alexandra J and Joshi, Shakchhi and Baron, Heide F and Drijvers, Jefte M and Georgiev, Peter and Ringel, Alison E and Zaganjor, Elma and McBrayer, Samuel K and Sorger, Peter K and Sharpe, Arlene H and Wucherpfennig, Kai W and Santagata, Sandro and Agar, Nathalie Y R and Suv{\`a}, Mario L and Haigis, Marcia C}
}
@article {1656929,
	title = {Polarity protein SCRIB interacts with SLC3A2 to regulate proliferation and tamoxifen resistance in ER+ breast cancer},
	journal = {Commun Biol},
	volume = {5},
	number = {1},
	year = {2022},
	month = {2022 05 02},
	pages = {403},
	abstract = {Estrogen receptor (ER) positive breast cancer represents 75\% of all breast cancers in women. Although patients with ER+ cancers receive endocrine therapies, more than 30\% develop resistance and succumb to the disease, highlighting the need to understand endocrine resistance. Here we show an unexpected role for the cell polarity protein SCRIB as a tumor-promoter and a regulator of endocrine resistance in ER-positive breast cancer cells. SCRIB expression is induced by estrogen signaling in a MYC-dependent manner. SCRIB interacts with SLC3A2, a heteromeric component of leucine amino acid transporter SLC7A5. SLC3A2 binds to the N-terminus of SCRIB to facilitate the formation of SCRIB/SLC3A2/LLGL2/SLC7A5 quaternary complex required for membrane localization of the amino acid transporter complex. Both SCRIB and SLC3A2 are required for cell proliferation and tamoxifen resistance in ER+ cells identifying a new role for the SCRIB/SLC3A2 complex in ER+ breast cancer.},
	keywords = {Breast Neoplasms, Cell Proliferation, Cytoskeletal Proteins, Drug Resistance, Neoplasm, Estrogens, Female, Fusion Regulatory Protein 1, Heavy Chain, Humans, Large Neutral Amino Acid-Transporter 1, Membrane Proteins, Receptors, Estrogen, Tamoxifen, Tumor Suppressor Proteins},
	issn = {2399-3642},
	doi = {10.1038/s42003-022-03363-3},
	author = {Saito, Yasuhiro and Matsuda, Shiori and Ohnishi, Naomi and Endo, Keiko and Ashitani, Sanae and Ohishi, Maki and Ueno, Ayano and Tomita, Masaru and Ueda, Koji and Soga, Tomoyoshi and Muthuswamy, Senthil K}
}
@article {1656928,
	title = {Reading oscillatory instructions: How cells achieve time-dependent responses to oscillating transcription factors},
	journal = {Curr Opin Cell Biol},
	volume = {77},
	year = {2022},
	month = {2022 08},
	pages = {102099},
	keywords = {Transcription Factors},
	issn = {1879-0410},
	doi = {10.1016/j.ceb.2022.102099},
	author = {Venkatachalam, Veena and Jambhekar, Ashwini and Lahav, Galit}
}
@article {1656924,
	title = {Single cell spatial analysis reveals the topology of immunomodulatory purinergic signaling in glioblastoma},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 Aug 16},
	pages = {4814},
	abstract = {How the glioma immune microenvironment fosters tumorigenesis remains incompletely defined. Here, we use single-cell RNA-sequencing and multiplexed tissue-imaging to characterize the composition, spatial organization, and clinical significance of extracellular purinergic signaling in glioma. We show that microglia are the predominant source of CD39, while tumor cells principally express CD73. In glioblastoma, CD73 is associated with EGFR amplification, astrocyte-like differentiation, and increased adenosine, and is linked to hypoxia. Glioblastomas enriched for CD73 exhibit inflammatory microenvironments, suggesting that purinergic signaling regulates immune adaptation. Spatially-resolved single-cell analyses demonstrate a strong spatial correlation between tumor-CD73 and microglial-CD39, with proximity associated with poor outcomes. Similar spatial organization is present in pediatric high-grade gliomas including H3K27M-mutant diffuse midline glioma. These data reveal that purinergic signaling in gliomas is shaped by genotype, lineage, and functional state, and that core enzymes expressed by tumor and myeloid cells are organized to promote adenosine-rich microenvironments potentially amenable to therapeutic targeting.},
	keywords = {5{\textquoteright}-Nucleotidase, Adenosine, Child, Glioblastoma, Glioma, Humans, Single-Cell Analysis, Spatial Analysis, Tumor Microenvironment},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-32430-w},
	author = {Coy, Shannon and Wang, Shu and Stopka, Sylwia A and Lin, Jia-Ren and Yapp, Clarence and Ritch, Cecily C and Salhi, Lisa and Baker, Gregory J and Rashid, Rumana and Baquer, Gerard and Regan, Michael and Khadka, Prasidda and Cole, Kristina A and Hwang, Jaeho and Wen, Patrick Y and Bandopadhayay, Pratiti and Santi, Mariarita and De Raedt, Thomas and Ligon, Keith L and Agar, Nathalie Y R and Sorger, Peter K and Touat, Mehdi and Santagata, Sandro}
}
@article {1656922,
	title = {STING agonism enhances anti-tumor immune responses and therapeutic efficacy of PARP inhibition in BRCA-associated breast cancer},
	journal = {NPJ Breast Cancer},
	volume = {8},
	number = {1},
	year = {2022},
	month = {2022 Sep 06},
	pages = {102},
	abstract = {Poly (ADP-ribose) polymerase (PARP) inhibitors exert their efficacy via synthetic lethal effects and by inducing cGAS/STING-mediated immune responses. We demonstrate that compared to monotherapies, combined PARP inhibition and STING agonism results in increased STING pathway activation, greater cytotoxic T-cell recruitment and enhanced dendritic cell activation in BRCA1-deficient breast cancer models. The combination markedly improved anti-tumor efficacy in vivo, with evidence of complete tumor clearance, prolongation of survival and induction of immunologic memory.},
	issn = {2374-4677},
	doi = {10.1038/s41523-022-00471-5},
	author = {Pantelidou, Constantia and Jadhav, Heta and Kothari, Aditi and Liu, Renyan and Wulf, Gerburg M and Guerriero, Jennifer L and Shapiro, Geoffrey I}
}
@article {1656925,
	title = {Targeting DNA Repair with Combined Inhibition of NHEJ and MMEJ Induces Synthetic Lethality in TP53-Mutant Cancers},
	journal = {Cancer Res},
	volume = {82},
	number = {20},
	year = {2022},
	month = {2022 Oct 17},
	pages = {3815-3829},
	abstract = {UNLABELLED: DNA repair pathway inhibitors are a new class of anticancer drugs that are advancing in clinical trials. Peposertib is an inhibitor of DNA-dependent protein kinase (DNA-PK), which is a key driver of nonhomologous end-joining (NHEJ). To identify regulators of response to peposertib, we performed a genome-wide CRISPR knockout screen and found that loss of POLQ (polymerase theta, POLθ) and other genes in the microhomology-mediated end-joining (MMEJ) pathway are key predictors of sensitivity to DNA-PK inhibition. Simultaneous disruption of two DNA repair pathways via combined treatment with peposertib plus a POLθ inhibitor novobiocin exhibited synergistic synthetic lethality resulting from accumulation of toxic levels of DNA double-strand break end resection. TP53-mutant tumor cells were resistant to peposertib but maintained elevated expression of POLQ and increased sensitivity to novobiocin. Consequently, the combination of peposertib plus novobiocin resulted in synthetic lethality in TP53-deficient tumor cell lines, organoid cultures, and patient-derived xenograft models. Thus, the combination of a targeted DNA-PK/NHEJ inhibitor with a targeted POLθ/MMEJ inhibitor may provide a rational treatment strategy for TP53-mutant solid tumors.

SIGNIFICANCE: Combined inhibition of NHEJ and MMEJ using two nontoxic, targeted DNA repair inhibitors can effectively induce toxic DNA damage to treat TP53-deficient cancers.},
	keywords = {DNA, DNA End-Joining Repair, DNA Repair, DNA-Activated Protein Kinase, DNA-Directed DNA Polymerase, Humans, Neoplasms, Novobiocin, Pyridazines, Quinazolines, Synthetic Lethal Mutations, Tumor Suppressor Protein p53},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-22-1124},
	author = {Patterson-Fortin, Jeffrey and Bose, Arindam and Tsai, Wei-Chih and Grochala, Carter and Nguyen, Huy and Zhou, Jia and Parmar, Kalindi and Lazaro, Jean-Bernard and Liu, Joyce and McQueen, Kelsey and Shapiro, Geoffrey I and Kozono, David and D{\textquoteright}Andrea, Alan D}
}
@article {1656927,
	title = {Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8 T~cells},
	journal = {Cell Metab},
	volume = {34},
	number = {8},
	year = {2022},
	month = {2022 08 02},
	pages = {1137-1150.e6},
	abstract = {The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T~cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T~cells, we establish an in~vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T~cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T~cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T~cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T~cells to retain cytotoxicity and overcome a lactate-enriched TME.},
	keywords = {CD8-Positive T-Lymphocytes, Humans, Immunity, Lactic Acid, Neoplasms, Pyruvate Carboxylase, Pyruvic Acid, Succinic Acid, Tumor Microenvironment},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2022.06.008},
	author = {Elia, Ilaria and Rowe, Jared H and Johnson, Sheila and Joshi, Shakchhi and Notarangelo, Giulia and Kurmi, Kiran and Weiss, Sarah and Freeman, Gordon J and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1641530,
	title = {A human breast atlas integrating single-cell proteomics and transcriptomics},
	journal = {Developmental Cell},
	volume = {57},
	year = {2022},
	pages = {1-21},
	abstract = {The breast is a dynamic organ whose response to physiological and pathophysiological conditions alters its disease susceptibility, yet the specific effects of these clinical variables on cell state remain poorly annotated. We present a unified, high-resolution breast atlas by integrating single-cell RNA-seq,\&nbsp;mass cytometry, and cyclic immunofluorescence, encompassing a myriad of states. We define cell subtypes within the alveolar, hormone-sensing, and basal epithelial lineages, delineating associations of several subtypes with cancer risk factors, including age, parity, and\&nbsp;BRCA2\&nbsp;germline mutation. Of particular interest is a subset of alveolar cells termed basal-luminal (BL) cells, which exhibit poor transcriptional lineage fidelity, accumulate with age, and carry a gene signature associated with basal-like breast cancer. We further utilize a medium-depletion approach to identify molecular factors regulating cell-subtype proportion in organoids. Together, these data are a rich resource to elucidate diverse mammary cell states.},
	url = {https://www.sciencedirect.com/science/article/pii/S1534580722003318?dgcid=author},
	author = {Gray, G. Kenneth and Li, Carman Man-Chung and Rosenbluth, Jennifer M and Selfors, Laura M and Girnius, Nomeda and Lin, Jia-Ren and Schackmann, Ron C J and Goh, Walter L and Moore, Kaitlin and Shapiro, Hana and Mei, Shaolin and D{\textquoteright}Andrea, Kurt and Nathanson, Katherine L and Sorger, Peter K and Santagata, Sandro and Regev, Aviv and Garber, Judy E and Dillon, Deborah A and Brugge, Joan S}
}
@article {1641521,
	title = {Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts},
	journal = {Oncogene},
	volume = {41},
	number = {1},
	year = {2022},
	month = {2022 01},
	pages = {112-124},
	abstract = {Intratumoral heterogeneity has been described for various tumor types and models of human cancer, and can have profound effects on tumor progression and drug resistance. This study describes an in-depth analysis of molecular and functional heterogeneity among subclonal populations (SCPs) derived from a single triple-negative breast cancer cell line, including copy number analysis, whole-exome and RNA sequencing, proteome analysis, and barcode analysis of clonal dynamics, as well as functional assays. The SCPs were found to have multiple unique genetic alterations and displayed significant variation in anchorage independent growth and tumor forming ability. Analyses of clonal dynamics in SCP mixtures using DNA barcode technology revealed selection for distinct clonal populations in different in vitro and in vivo environmental contexts, demonstrating that in vitro propagation of cancer cell lines using different culture conditions can contribute to the establishment of unique strains. These analyses also revealed strong enrichment of a single SCP during the development of xenograft tumors in immune-compromised mice. This SCP displayed attenuated interferon signaling in vivo and reduced sensitivity to the antiproliferative effects of type I interferons. Reduction in interferon signaling was found to provide a selective advantage within the xenograft microenvironment specifically. In concordance with the previously described role of interferon signaling as tumor suppressor, these findings suggest that similar selective pressures may be operative in human cancer and patient-derived xenograft models.},
	keywords = {Animals, Genetic Heterogeneity, Humans, Mice, Mutation, Triple Negative Breast Neoplasms, Tumor Microenvironment},
	issn = {1476-5594},
	doi = {10.1038/s41388-021-02075-y},
	author = {Kuiken, Hendrik J and Dhakal, Sabin and Selfors, Laura M and Friend, Chandler M and Zhang, Tian and Callari, Maurizio and Schackmann, Ron C J and Gray, G Kenneth and Crowdis, Jett and Bhang, Hyo-Eun C and Baslan, Timour and Stegmeier, Frank and Gygi, Steven P and Caldas, Carlos and Brugge, Joan S}
}
@article {1641520,
	title = {A vaccine targeting resistant tumours by dual T cell plus NK cell attack},
	journal = {Nature},
	year = {2022},
	month = {2022 May 25},
	abstract = {Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a cancer vaccine that induces a coordinated attack by diverse T cell and natural killer (NK) cell populations. The vaccine targets the MICA and MICB (MICA/B) stress proteins expressed by many human cancers as a result of DNA damage2. MICA/B serve as ligands for the activating NKG2D receptor on T cells and NK cells, but tumours evade immune recognition by proteolytic MICA/B cleavage3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumour cells by inhibiting proteolytic shedding, enhance presentation of tumour antigens by dendritic cells to T cells and augment the cytotoxic function of NK cells. Notably, this vaccine maintains efficacy against MHC class I-deficient tumours resistant to cytotoxic T cells through the coordinated action of NK cells and CD4+ T cells. The vaccine is also efficacious in a clinically important setting: immunization following surgical removal of primary, highly metastatic tumours inhibits the later outgrowth of metastases. This vaccine design enables protective immunity even against tumours with common escape mutations.},
	issn = {1476-4687},
	doi = {10.1038/s41586-022-04772-4},
	author = {Badrinath, Soumya and Dellacherie, Maxence O and Li, Aileen and Zheng, Shiwei and Zhang, Xixi and Sobral, Miguel and Pyrdol, Jason W and Smith, Kathryn L and Lu, Yuheng and Haag, Sabrina and Ijaz, Hamza and Connor-Stroud, Fawn and Tsuneyasu Kaisho and Dranoff, Glenn and Yuan, Guo-Cheng and Mooney, David J and Wucherpfennig, Kai W}
}
@article {1640668,
	title = {Cancer patient survival can be parametrized to improve trial precision and reveal time-dependent therapeutic effects},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 02 15},
	pages = {873},
	abstract = {Individual participant data (IPD) from oncology clinical trials is invaluable for identifying factors that influence trial success and failure, improving trial design and interpretation, and comparing pre-clinical studies to clinical outcomes. However, the IPD used to generate published survival curves are not generally publicly available. We impute survival IPD from ~500 arms of Phase 3 oncology trials (representing ~220,000 events) and find that they are well fit by a two-parameter Weibull distribution. Use of Weibull functions with overall survival significantly increases the precision of small arms typical of early phase trials: analysis of a 50-patient trial arm using parametric forms is as precise as traditional, non-parametric analysis of a 90-patient arm. We also show that frequent deviations from the Cox proportional hazards assumption, particularly in trials of immune checkpoint inhibitors, arise from time-dependent therapeutic effects. Trial duration therefore has an underappreciated impact on the likelihood of success.},
	keywords = {Cancer Survivors, Clinical Trials as Topic, Humans, Kaplan-Meier Estimate, Models, Statistical, Neoplasms, Proportional Hazards Models, Research Design},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-28410-9},
	author = {Plana, Deborah and Fell, Geoffrey and Alexander, Brian M and Palmer, Adam C and Sorger, Peter K}
}
@article {1640659,
	title = {Copper induces cell death by targeting lipoylated TCA cycle proteins},
	journal = {Science},
	volume = {375},
	number = {6586},
	year = {2022},
	month = {2022 03 18},
	pages = {1254-1261},
	abstract = {Copper is an essential cofactor for all organisms, and yet it becomes toxic if concentrations exceed a threshold maintained by evolutionarily conserved homeostatic mechanisms. How excess copper induces cell death, however, is unknown. Here, we show in human cells that copper-dependent, regulated cell death is distinct from known death mechanisms and is dependent on mitochondrial respiration. We show that copper-dependent death occurs by means of direct binding of copper to lipoylated components of the tricarboxylic acid (TCA) cycle. This results in lipoylated protein aggregation and subsequent iron-sulfur cluster protein loss, which leads to proteotoxic stress and ultimately cell death. These findings may explain the need for ancient copper homeostatic mechanisms.},
	keywords = {Animals, Cell Respiration, Citric Acid Cycle, Copper, Dihydrolipoyllysine-Residue Acetyltransferase, Hepatolenticular Degeneration, Homeostasis, Humans, Hydrazines, Ionophores, Iron-Sulfur Proteins, Lipoylation, Metabolic Networks and Pathways, Mice, Mitochondria, Regulated Cell Death},
	issn = {1095-9203},
	doi = {10.1126/science.abf0529},
	author = {Tsvetkov, Peter and Coy, Shannon and Petrova, Boryana and Dreishpoon, Margaret and Verma, Ana and Abdusamad, Mai and Rossen, Jordan and Joesch-Cohen, Lena and Humeidi, Ranad and Spangler, Ryan D and Eaton, John K and Frenkel, Evgeni and Kocak, Mustafa and Corsello, Steven M and Lutsenko, Svetlana and Kanarek, Naama and Santagata, Sandro and Golub, Todd R}
}
@article {1640666,
	title = {Genetic analysis of cancer drivers reveals cohesin and CTCF as suppressors of PD-L1},
	journal = {Proc Natl Acad Sci U S A},
	volume = {119},
	number = {7},
	year = {2022},
	month = {2022 02 15},
	abstract = {Immune evasion is a significant contributor to tumor evolution, and the immunoinhibitory axis PD-1/PD-L1 is a frequent mechanism employed to escape tumor immune surveillance. To identify cancer drivers involved in immune evasion, we performed a CRISPR-Cas9 screen of tumor suppressor genes regulating the basal and interferon (IFN)-inducible cell surface levels of PD-L1. Multiple regulators of PD-L1 were identified, including IRF2, ARID2, KMT2D, and AAMP. We also identified CTCF and the cohesin complex proteins, known regulators of chromatin architecture and transcription, among the most potent negative regulators of PD-L1 cell surface expression. Additionally, loss of the cohesin subunit RAD21 was shown to up-regulate PD-L2 and MHC-I surface expression. PD-L1 and MHC-I suppression by cohesin were shown to be conserved in mammary epithelial and myeloid cells. Comprehensive examination of the transcriptional effect of STAG2 deficiency in epithelial and myeloid cells revealed an activation of strong IFN and NF-κB expression signatures. Inhibition of JAK-STAT or NF-κB pathways did not result in rescue of PD-L1 up-regulation in RAD21-deficient cells, suggesting more complex or combinatorial mechanisms at play. Discovery of the PD-L1 and IFN up-regulation in cohesin-mutant cells expands our understanding of the biology of cohesin-deficient cells as well as molecular regulation of the PD-L1 molecule.},
	keywords = {B7-H1 Antigen, CCCTC-Binding Factor, Cell Cycle Proteins, Cell Line, Chromosomal Proteins, Non-Histone, Gene Expression Regulation, Neoplastic, Humans, Janus Kinases, Neoplasms, NF-kappa B, STAT Transcription Factors, Up-Regulation},
	issn = {1091-6490},
	doi = {10.1073/pnas.2120540119},
	author = {Oreskovic, Ena and Wheeler, Emily C and Mengwasser, Kristen E and Fujimura, Eric and Martin, Timothy D and Tothova, Zuzana and Elledge, Stephen J}
}
@article {1640663,
	title = {Louder for longer: Myc amplifies gene expression by extended transcriptional bursting},
	journal = {Cell Rep},
	volume = {38},
	number = {9},
	year = {2022},
	month = {2022 03 01},
	pages = {110470},
	abstract = {Transcription is a complex, dynamic process. Using live single-cell measurements, Patange et\&nbsp;al. show, in a recent issue of Cell Reports, that elevated levels of the transcription factor MYC enhance target gene RNA production by increasing the duration but not frequency of transcriptional bursts.},
	keywords = {Gene Expression, Gene Expression Regulation, Transcription Factors},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2022.110470},
	author = {Lu, Dan and Jambhekar, Ashwini and Lahav, Galit}
}
@article {1640661,
	title = {MITI minimum information guidelines for highly multiplexed tissue images},
	journal = {Nat Methods},
	volume = {19},
	number = {3},
	year = {2022},
	month = {2022 Mar},
	pages = {262-267},
	issn = {1548-7105},
	doi = {10.1038/s41592-022-01415-4},
	author = {Schapiro, Denis and Yapp, Clarence and Sokolov, Artem and Reynolds, Sheila M and Chen, Yu-An and Sudar, Damir and Xie, Yubin and Muhlich, Jeremy and Arias-Camison, Raquel and Arena, Sarah and Taylor, Adam J and Nikolov, Milen and Tyler, Madison and Lin, Jia-Ren and Burlingame, Erik A and Human Tumor Atlas Network and Chang, Young H and Farhi, Samouil L and Thorsson, V{\'e}steinn and Venkatamohan, Nithya and Drewes, Julia L and Pe{\textquoteright}er, Dana and Gutman, David A and Herrmann, Markus D and Nils Gehlenborg and Bankhead, Peter and Roland, Joseph T and Herndon, John M and Snyder, Michael P and Angelo, Michael and Nolan, Garry and Swedlow, Jason R and Schultz, Nikolaus and Merrick, Daniel T and Mazzili, Sarah A and Cerami, Ethan and Rodig, Scott J and Santagata, Sandro and Sorger, Peter K}
}
@article {1640664,
	title = {Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations},
	journal = {Nat Biotechnol},
	volume = {40},
	number = {7},
	year = {2022},
	month = {2022 07},
	pages = {1030-1034},
	abstract = {The combination of single-cell transcriptomics with mitochondrial DNA variant detection can be used to establish lineage relationships in primary human cells, but current methods are not scalable to interrogate complex tissues. Here, we combine common 3{\textquoteright} single-cell RNA-sequencing protocols with mitochondrial transcriptome enrichment to increase coverage by more than 50-fold, enabling high-confidence mutation detection. The method successfully identifies skewed immune-cell expansions in primary human clonal hematopoiesis.},
	keywords = {DNA, Mitochondrial, High-Throughput Nucleotide Sequencing, Humans, Mitochondria, Mutation, Sequence Analysis, RNA, Single-Cell Analysis},
	issn = {1546-1696},
	doi = {10.1038/s41587-022-01210-8},
	author = {Miller, Tyler E and Lareau, Caleb A and Verga, Julia A and DePasquale, Erica A K and Liu, Vincent and Ssozi, Daniel and Sandor, Katalin and Yin, Yajie and Ludwig, Leif S and El Farran, Chadi A and Morgan, Duncan M and Satpathy, Ansuman T and Griffin, Gabriel K and Lane, Andrew A and Love, J Christopher and Bernstein, Bradley E and Sankaran, Vijay G and van Galen, Peter}
}
@article {1640658,
	title = {Preclinical modeling of leiomyosarcoma identifies susceptibility to transcriptional CDK inhibitors through antagonism of E2F-driven oncogenic gene expression},
	journal = {Clin Cancer Res},
	year = {2022},
	month = {2022 Mar 24},
	abstract = {PURPOSE: Leiomyosarcoma (LMS) is a neoplasm characterized by smooth muscle differentiation, complex copy-number alterations, tumor suppressor loss and the absence of recurrent driver mutations. Clinical management for advanced disease relies on the use of empiric cytotoxic chemotherapy with limited activity, and novel targeted therapies supported by preclinical research on LMS biology are urgently needed. A lack of fidelity of established LMS cell lines to their mesenchymal neoplasm of origin has limited translational understanding of this disease, and few other preclinical models have been established. Here, we characterize LMS patient derived xenograft (PDX) models of LMS, assessing fidelity to their tumors of origin and performing preclinical evaluation of candidate therapies. EXPERIMENTAL DESIGN: We implanted 49 LMS surgical samples into immunocompromised mice. Engrafting tumors were characterized by histology, targeted next-generation sequencing, RNA-seq and ultra-low passage whole-genome sequencing. Candidate therapies were selected based on prior evidence of pathway activation or high-throughput dynamic BH3 profiling. RESULTS: We show that LMS PDX maintain the histologic appearance, copy-number alterations and transcriptional program of their parental tumors across multiple xenograft passages. Transcriptionally, LMS PDX co-cluster with paired LMS patient-derived samples and differ primarily in host-related immunologic and microenvironment signatures. We identify susceptibility of LMS PDX to transcriptional CDK inhibition, which disrupts an E2F-driven oncogenic transcriptional program and inhibits tumor growth. CONCLUSIONS: Our results establish LMS PDX as valuable preclinical models and identify strategies to discover novel vulnerabilities in this disease. These data support the clinical assessment of transcriptional CDK inhibitors as a therapeutic strategy for LMS patients.},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-21-3523},
	author = {Hemming, Matthew L and Bhola, Patrick and Loycano, Michael A and Anderson, Justin A and Taddei, Madeleine L and Doyle, Leona A and Lavrova, Elizaveta and Andersen, Jessica L and Klega, Kelly S and Benson, Morgan R and Crompton, Brian D and Raut, Chandrajit P and George, Suzanne and Letai, Anthony and Demetri, George D and Sicinska, Ewa}
}
@article {1640657,
	title = {Single-Cell Multiomics Reveals Clonal T-Cell Expansions and Exhaustion in Blastic Plasmacytoid Dendritic Cell Neoplasm},
	journal = {Front Immunol},
	volume = {13},
	year = {2022},
	month = {2022},
	pages = {809414},
	abstract = {The immune system represents a major barrier to cancer progression, driving the evolution of immunoregulatory interactions between malignant cells and T-cells in the tumor environment. Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare acute leukemia with plasmacytoid dendritic cell (pDC) differentiation, provides a unique opportunity to study these interactions. pDCs are key producers of interferon alpha (IFNA) that play an important role in T-cell activation at the interface between the innate and adaptive immune system. To assess how uncontrolled proliferation of malignant BPDCN cells affects the tumor environment, we catalog immune cell heterogeneity in the bone marrow (BM) of five healthy controls and five BPDCN patients by analyzing 52,803 single-cell transcriptomes, including 18,779 T-cells. We test computational techniques for robust cell type classification and find that T-cells in BPDCN patients consistently upregulate interferon alpha (IFNA) response and downregulate tumor necrosis factor alpha (TNFA) pathways. Integrating transcriptional data with T-cell receptor sequencing via shared barcodes reveals significant T-cell exhaustion in BPDCN that is positively correlated with T-cell clonotype expansion. By highlighting new mechanisms of T-cell exhaustion and immune evasion in BPDCN, our results demonstrate the value of single-cell multiomics to understand immune cell interactions in the tumor environment.},
	keywords = {Dendritic Cells, Humans, Interferon-alpha, Myeloproliferative Disorders, Skin Neoplasms, T-Lymphocytes},
	issn = {1664-3224},
	doi = {10.3389/fimmu.2022.809414},
	author = {DePasquale, Erica A K and Ssozi, Daniel and Ainciburu, Marina and Good, Jonathan and Noel, Jenny and Villanueva, Martin A and Couturier, Charles P and Shalek, Alex K and Aranki, Sary F and Mallidi, Hari R and Griffin, Gabriel K and Lane, Andrew A and van Galen, Peter}
}
@article {1640665,
	title = {Single-cell tumor-immune microenvironment of BRCA1/2 mutated high-grade serous ovarian cancer},
	journal = {Nat Commun},
	volume = {13},
	number = {1},
	year = {2022},
	month = {2022 02 11},
	pages = {835},
	abstract = {The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the~BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.},
	keywords = {BRCA1 Protein, BRCA2 Protein, Carcinoma, Ovarian Epithelial, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cystadenocarcinoma, Serous, Female, Genes, BRCA1, Genes, BRCA2, Genotype, Homologous Recombination, Humans, Mutation, Ovarian Neoplasms, Prognosis, Proteomics, Tumor Microenvironment},
	issn = {2041-1723},
	doi = {10.1038/s41467-022-28389-3},
	author = {Launonen, I-M and Lyytik{\"a}inen, N and Casado, J and Anttila, E A and Szab{\'o}, A and Haltia, U-M and Jacobson, C A and Lin, J R and Maliga, Z and Howitt, B E and Strickland, K C and Santagata, S and Elias, K and D{\textquoteright}Andrea, A D and Konstantinopoulos, P A and Sorger, P K and F{\"a}rkkil{\"a}, A}
}
@article {1640660,
	title = {Temporal and spatial topography of cell proliferation in cancer},
	journal = {Nat Cell Biol},
	volume = {24},
	number = {3},
	year = {2022},
	month = {2022 Mar},
	pages = {316-326},
	abstract = {Proliferation is a fundamental trait of cancer cells, but its properties and spatial organization in tumours are poorly characterized. Here we use highly multiplexed tissue imaging to perform single-cell quantification of cell cycle regulators and then develop robust, multivariate, proliferation metrics. Across diverse cancers, proliferative architecture is organized at two spatial scales: large domains, and smaller niches enriched for specific immune lineages. Some tumour cells express cell cycle regulators in the (canonical) patterns expected of freely growing cells, a phenomenon we refer to as {\textquoteright}cell cycle coherence{\textquoteright}. By contrast, the cell cycles of other tumour cell populations are skewed towards specific phases or exhibit non-canonical (incoherent) marker combinations. Coherence varies across space, with changes in oncogene activity and therapeutic intervention, and is associated with aggressive tumour behaviour. Thus, multivariate measures from high-plex tissue images capture clinically significant features of cancer proliferation, a fundamental step in enabling more precise use of anti-cancer therapies.},
	keywords = {Cell Cycle, Cell Proliferation, Humans, Neoplasms},
	issn = {1476-4679},
	doi = {10.1038/s41556-022-00860-9},
	author = {Gaglia, Giorgio and Kabraji, Sheheryar and Rammos, Danae and Dai, Yang and Verma, Ana and Wang, Shu and Mills, Caitlin E and Chung, Mirra and Bergholz, Johann S and Coy, Shannon and Lin, Jia-Ren and Jeselsohn, Rinath and Metzger, Otto and Winer, Eric P and Dillon, Deborah A and Zhao, Jean J and Sorger, Peter K and Santagata, Sandro}
}
@article {1640662,
	title = {Transcriptome profiling of ADAR1 targets in triple-negative breast cancer cells reveals mechanisms for regulating growth and invasion},
	journal = {Mol Cancer Res},
	year = {2022},
	month = {2022 Mar 04},
	abstract = {ADARs catalyze Adenosine-to-Inosine (A-to-I) editing of double-stranded RNA and regulate global gene expression output through interactions with RNA and other proteins. ADARs play important roles in development and disease, and previous work has shown that ADAR1 is oncogenic in a growing list of cancer types. Here we show that ADAR1 is a critical gene for triple-negative breast cancer cells, as ADAR1 loss results in reduced growth (viability and cell cycle progression), invasion, and mammosphere formation. Whole transcriptome sequencing analyses demonstrate that ADAR1 regulates both coding and non-coding targets by altering gene expression level, A-to-I editing, and splicing. We determine that a recoding edit in filamin B (FLNB chr3:58156064) reduces the tumor suppressive activities of the protein to promote growth and invasion. We also show that several tumor suppressor microRNAs are upregulated upon ADAR1 loss and suppress cell cycle progression and invasion. Implications: This work describes several novel mechanisms of ADAR1-mediated oncogenesis in triple-negative breast cancer, providing support to strategies targeting ADAR1 in this aggressive cancer type that has few treatment options.},
	issn = {1557-3125},
	doi = {10.1158/1541-7786.MCR-21-0604},
	author = {Baker, Allison R and Miliotis, Christos and Ram{\'\i}rez-Moya, Julia and Marc, Talia and Vlachos, Ioannis S and Santisteban, Pilar and Slack, Frank J}
}
@article {1638634,
	title = {Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis},
	journal = {Cell},
	volume = {185},
	number = {9},
	year = {2022},
	month = {2022 Apr 28},
	pages = {1521-1538.e18},
	abstract = {Interest in harnessing natural killer (NK) cells for cancer immunotherapy is rapidly growing. However, efficacy of NK cell-based immunotherapy remains limited in most trials. Strategies to augment the killing efficacy of NK cells are thus much needed. In the current study, we found that mitochondrial apoptosis (mtApoptosis) pathway is essential for efficient NK killing, especially at physiologically relevant effector-to-target ratios. Furthermore, NK cells can prime cancer cells for mtApoptosis and mitochondrial priming status affects cancer-cell susceptibility to NK-mediated killing. Interestingly, pre-activating NK cells confers on them resistance to BH3 mimetics. Combining BH3 mimetics with NK cells synergistically kills cancer cells in\&nbsp;vitro and suppresses tumor growth in\&nbsp;vivo. The ideal BH3 mimetic to use in such an approach can be predicted by BH3 profiling. We herein report a rational and precision strategy to augment NK-based immunotherapy, which may be adaptable to T\&nbsp;cell-based immunotherapies as well.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2022.03.030},
	author = {Pan, Rongqing and Ryan, Jeremy and Deng Pan and Wucherpfennig, Kai W and Letai, Anthony}
}
@article {1638630,
	title = {Breakage of cytoplasmic chromosomes by pathological DNA base excision repair},
	journal = {Nature},
	year = {2022},
	month = {2022 Apr 27},
	abstract = {Chromothripsis is a catastrophic mutational process that promotes tumorigenesis and causes congenital disease1-4. Chromothripsis originates from aberrations of nuclei called micronuclei or chromosome bridge5-8. These structures have fragile nuclear envelopes (NEs) that spontaneously rupture9,10, leading to DNA damage when chromatin is exposed to the interphase cytoplasm. Here, we identify a mechanism explaining a major fraction of this DNA damage. Micronuclei accumulate large amounts of RNA-DNA hybrids, which are edited by ADAR enzymes (adenine deaminases acting on RNA) to generate deoxyinosine (dI). dI is then converted into abasic sites by a DNA base excision repair (BER) glycosylase, MPG (N-methyl-purine DNA glycosylase)11,12. These abasic sites are cleaved by the BER endonuclease, APE1 (apurinic/apyrimidinic endonuclease)12, creating single-strand DNA nicks that can be converted to DNA double strand breaks by DNA replication or when closely spaced nicks occur on opposite strands13,14. This model predicts that MPG should be able to remove the dI base from the DNA strand of RNA-DNA hybrids, which we demonstrate using pure proteins and oligonucleotide substrates. These findings identify a mechanism for fragmentation of micronuclear chromosomes, an important step in generating chromothripsis. Rather than breaking any normal chromosome, we propose that the eukaryotic cytoplasm only damages chromosomes with preexisting defects such as the DNA base abnormality described here.},
	issn = {1476-4687},
	doi = {10.1038/s41586-022-04767-1},
	author = {Tang, Shangming and Stokasimov, Ema and Cui, Yuxiang and Pellman, David}
}
@article {1638635,
	title = {Insights into immune escape during tumor evolution and response to immunotherapy using a rat model of breast cancer},
	journal = {Cancer Immunol Res},
	year = {2022},
	month = {2022 Apr 21},
	abstract = {Animal models are critical for the preclinical validation of cancer immunotherapies. Unfortunately, mouse breast cancer models do not faithfully reproduce the molecular subtypes and immune environment of the human disease. In particular, there are no good murine models of estrogen receptor-positive (ER+) breast cancer, the predominant subtype in patients. Here, we show that Nitroso-N-methylurea-induced mammary tumors in outbred Sprague-Dawley rats recapitulate the heterogeneity for mutational profiles, ER expression, and immune evasive mechanisms observed in human breast cancer. We demonstrate the utility of this model for preclinical studies by dissecting mechanisms of response to immunotherapy using combination TGFBR inhibition and PD-L1 blockade. Short-term treatment of early-stage tumors induced durable responses. Gene expression profiling and spatial mapping classified tumors as inflammatory and non-inflammatory, and identified IFN, TCR and BCR signaling, CD74/MHC II, and epithelium-interacting CD8+ T cells as markers of response, whereas the complement system, M2 macrophage phenotype, and translation in mitochondria were associated with resistance. We found that the expression of CD74 correlated with leukocyte fraction and TCR diversity in human breast cancer. We identified a subset of rat ER+ tumors marked by expression of antigen-processing genes that had an active immune environment and responded to treatment. A gene signature characteristic of these tumors predicted disease-free survival in ER+ Luminal A breast cancer patients and overall survival in metastatic breast cancer patients receiving anti-PD-L1 therapy. We demonstrate the usefulness of this preclinical model for immunotherapy and suggest examination to expand immunotherapy to a subset of patients with ER+ disease.},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-21-0804},
	author = {Gil Del Alcazar, Carlos R and Trinh, Anne and Aleckovic, Masa and Rojas Jimenez, Ernesto and Harper, Nicholas W and Oliphant, Michael Uj and Xie, Shanshan and Krop, Ethan D and Lulseged, Bethlehem and Murphy, Katherine C and Keenan, Tanya E and Van Allen, Eliezer M and Tolaney, Sara M and Freeman, Gordon J and Dillon, Deborah A and Muthuswamy, Senthil K and Polyak, Kornelia}
}
@article {1638637,
	title = {Monocytes transition to macrophages within the inflamed vasculature via monocyte CCR2 and endothelial TNFR2},
	journal = {J Exp Med},
	volume = {219},
	number = {5},
	year = {2022},
	month = {2022 05 02},
	abstract = {Monocytes undergo phenotypic and functional changes in response to inflammatory cues, but the molecular signals that drive different monocyte states remain largely undefined. We show that monocytes acquire macrophage markers upon glomerulonephritis and may be derived from CCR2+CX3CR1+ double-positive monocytes, which are preferentially recruited, dwell within glomerular capillaries, and acquire proinflammatory characteristics in the nephritic kidney. Mechanistically, the transition to immature macrophages begins within the vasculature and relies on CCR2 in circulating cells and TNFR2 in parenchymal cells, findings that are recapitulated in vitro with monocytes cocultured with TNF-TNFR2-activated endothelial cells generating CCR2 ligands. Single-cell RNA sequencing of cocultures defines a CCR2-dependent monocyte differentiation path associated with the acquisition of immune effector functions and generation of CCR2 ligands. Immature macrophages are detected in the urine of lupus nephritis patients, and their frequency correlates with clinical disease. In conclusion, CCR2-dependent functional specialization of monocytes into macrophages begins within the TNF-TNFR2-activated vasculature and may establish a CCR2-based autocrine, feed-forward loop that amplifies renal inflammation.},
	keywords = {Endothelial Cells, Humans, Ligands, Macrophages, Monocytes, Receptors, CCR2, Receptors, Tumor Necrosis Factor, Type II},
	issn = {1540-9538},
	doi = {10.1084/jem.20210562},
	author = {Mysore, Vijayashree and Tahir, Suhail and Furuhashi, Kazuhiro and Jatin Arora and Rosetti, Florencia and Cullere, Xavier and Yazbeck, Pascal and Sekulic, Miroslav and Lemieux, Madeleine E and Raychaudhuri, Soumya and Horwitz, Bruce H and Mayadas, Tanya N}
}
@article {1638633,
	title = {Quiescent cancer cells resist T~cell attack by forming an immunosuppressive niche},
	journal = {Cell},
	volume = {185},
	number = {10},
	year = {2022},
	month = {2022 05 12},
	pages = {1694-1708.e19},
	abstract = {Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T~cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T~cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T~cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.},
	keywords = {Humans, Immunosuppressive Agents, Immunotherapy, Neoplasm Recurrence, Local, T-Lymphocytes, Triple Negative Breast Neoplasms, Tumor Microenvironment},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2022.03.033},
	author = {Baldominos, Pilar and Barbera-Mourelle, Alex and Barreiro, Olga and Huang, Yu and Wight, Andrew and Cho, Jae-Won and Zhao, Xi and Estivill, Guillem and Adam, Isam and Sanchez, Xavier and McCarthy, Shannon and Schaller, Julien and Khan, Zara and Ruzo, Albert and Pastorello, Ricardo and Richardson, Edward T and Dillon, Deborah and Montero-Llopis, Paula and Barroso-Sousa, Romualdo and Forman, Juliet and Shukla, Sachet A and Tolaney, Sara M and Mittendorf, Elizabeth A and von Andrian, Ulrich H and Wucherpfennig, Kai W and Hemberg, Martin and Agudo, Judith}
}
@article {1638636,
	title = {The Spatial Landscape of Progression and Immunoediting in Primary Melanoma at Single-Cell Resolution},
	journal = {Cancer Discov},
	volume = {12},
	number = {6},
	year = {2022},
	month = {2022 06 02},
	pages = {1518-1541},
	abstract = {Cutaneous melanoma is a highly immunogenic malignancy that is surgically curable at early stages but life-threatening when metastatic. Here we integrate high-plex imaging, 3D high-resolution microscopy, and spatially resolved microregion transcriptomics to study immune evasion and immunoediting in primary melanoma. We find that recurrent cellular neighborhoods involving tumor, immune, and stromal cells change significantly along a progression axis involving precursor states, melanoma in situ, and invasive tumor. Hallmarks of immunosuppression are already detectable in precursor regions. When tumors become locally invasive, a consolidated and spatially restricted suppressive environment forms along the tumor-stromal boundary. This environment is established by cytokine gradients that promote expression of MHC-II and IDO1, and by PD1-PDL1-mediated cell contacts involving macrophages, dendritic cells, and T cells. A few millimeters away, cytotoxic T cells synapse with melanoma cells in fields of tumor regression. Thus, invasion and immunoediting can coexist within a few millimeters of each other in a single specimen.

SIGNIFICANCE: The reorganization of the tumor ecosystem in primary melanoma is an excellent setting in which to study immunoediting and immune evasion. Guided by classic histopathology, spatial profiling of proteins and mRNA reveals recurrent morphologic and molecular features of tumor evolution that involve localized paracrine cytokine signaling and direct cell-cell contact. This article is highlighted in the In This Issue feature, p. 1397.},
	keywords = {Cytokines, Ecosystem, Humans, Melanoma, Skin Neoplasms},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-21-1357},
	author = {Nirmal, Ajit J and Maliga, Zoltan and Vallius, Tuulia and Quattrochi, Brian and Chen, Alyce A and Jacobson, Connor A and Pelletier, Roxanne J and Yapp, Clarence and Arias-Camison, Raquel and Chen, Yu-An and Lian, Christine G and Murphy, George F and Santagata, Sandro and Sorger, Peter K}
}
@article {1628685,
	title = {Functional precision oncology: Testing tumors with drugs to identify vulnerabilities and novel combinations},
	journal = {Cancer Cell},
	volume = {40},
	number = {1},
	year = {2022},
	month = {2022 Jan 10},
	pages = {26-35},
	abstract = {Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information to guide therapy. The heterogeneity of human cancer has led to the realization that personalized approaches are needed to improve treatment outcomes. Precision oncology has traditionally used static features of the tumor to dictate which therapies should be used. Static features can include expression of key targets or genomic analysis of mutations to identify therapeutically targetable "drivers." Although a surprisingly small proportion of individuals derive clinical benefit from the static approach, functional precision medicine can provide additional information regarding tumor vulnerabilities. We discuss emerging technologies for functional precision medicine as well as limitations and challenges in using these assays in the clinical trials that will be necessary to determine whether functional precision medicine can improve outcomes and eventually become a standard tool in clinical oncology.},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2021.12.004},
	author = {Letai, Anthony and Bhola, Patrick and Welm, Alana L}
}
@article {1628684,
	title = {Independent Drug Action in Combination Therapy: Implications for Precision Oncology},
	journal = {Cancer Discov},
	year = {2022},
	month = {2022 Jan 04},
	abstract = {Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-21-0212},
	author = {Plana, Deborah and Palmer, Adam C and Sorger, Peter K}
}
@article {1628686,
	title = {MCMICRO: a scalable, modular image-processing pipeline for multiplexed tissue imaging},
	journal = {Nat Methods},
	volume = {19},
	number = {3},
	year = {2022},
	month = {2022 03},
	pages = {311-315},
	abstract = {Highly multiplexed tissue imaging makes detailed molecular analysis of single cells possible in a preserved spatial context. However, reproducible analysis of large multichannel images poses a substantial computational challenge. Here, we describe a modular and open-source computational pipeline, MCMICRO, for performing the sequential steps needed to transform whole-slide images into single-cell data. We demonstrate the use of MCMICRO on tissue and tumor images acquired using multiple imaging platforms, thereby providing a solid foundation for the continued development of tissue imaging software.},
	keywords = {Diagnostic Imaging, Humans, Image Processing, Computer-Assisted, Neoplasms, Software},
	issn = {1548-7105},
	doi = {10.1038/s41592-021-01308-y},
	author = {Schapiro, Denis and Sokolov, Artem and Yapp, Clarence and Chen, Yu-An and Muhlich, Jeremy L and Hess, Joshua and Creason, Allison L and Nirmal, Ajit J and Baker, Gregory J and Nariya, Maulik K and Lin, Jia-Ren and Maliga, Zoltan and Jacobson, Connor A and Hodgman, Matthew W and Ruokonen, Juha and Farhi, Samouil L and Abbondanza, Domenic and McKinley, Eliot T and Persson, Daniel and Betts, Courtney and Sivagnanam, Shamilene and Regev, Aviv and Goecks, Jeremy and Coffey, Robert J and Coussens, Lisa M and Santagata, Sandro and Sorger, Peter K}
}
@article {1641522,
	title = {Clinical evaluation of BCL-2/XL levels pre- and post- HER2-targeted therapy},
	journal = {PLoS One},
	volume = {16},
	number = {5},
	year = {2021},
	month = {2021},
	pages = {e0251163},
	abstract = {Our previous pre-clinical work defined BCL-2 induction as a critical component of the adaptive response to lapatinib-mediated inhibition of HER2. To determine whether a similar BCL-2 upregulation occurs in lapatinib-treated patients, we evaluated gene expression within tumor biopsies, collected before and after lapatinib or trastuzumab treatment, from the TRIO-B-07 clinical trial (NCT$\#$00769470). We detected BCL2 mRNA upregulation in both HER2+/ER- as well as HER2+/ER+ patient tumors treated with lapatinib or trastuzumab. To address whether mRNA expression correlated with protein expression, we evaluated pre- and post-treatment tumors for BCL-2 via immunohistochemistry. Despite BCL2 mRNA upregulation within HER2+/ER- tumors, BCL-2 protein levels were undetectable in most of the lapatinib- or trastuzumab-treated HER2+/ER- tumors. BCL-2 upregulation was evident within the majority of lapatinib-treated HER2+/ER+ tumors and was often coupled with increased ER expression and decreased proliferation. Comparable BCL-2 upregulation was not observed within the trastuzumab-treated HER2+/ER+ tumors. Together, these results provide clinical validation of the BCL-2 induction associated with the adaptive response to lapatinib and support evaluation of BCL-2 inhibitors within the context of lapatinib and other HER2-targeted receptor tyrosine kinase inhibitors.},
	keywords = {Adult, Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Breast Neoplasms, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, Humans, Lapatinib, Middle Aged, Neoadjuvant Therapy, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-bcl-2, Quinazolines, Receptor, ErbB-2, RNA, Messenger, Trastuzumab, Up-Regulation},
	issn = {1932-6203},
	doi = {10.1371/journal.pone.0251163},
	author = {Zoeller, Jason J and Press, Michael F and Selfors, Laura M and Dering, Judy and Slamon, Dennis J and Hurvitz, Sara A and Brugge, Joan S}
}
@article {1638631,
	title = {A pan-cancer survey of cell line tumor similarity by feature-weighted molecular profiles},
	journal = {Cell Rep Methods},
	volume = {1},
	number = {2},
	year = {2021},
	month = {2021 Jun 21},
	pages = {100039},
	abstract = {Patient-derived cell lines are often used in pre-clinical cancer research, but some cell lines are too different from tumors to be good models. Comparison of genomic and expression profiles can guide the choice of pre-clinical models, but typically not all features are equally relevant. We present TumorComparer, a computational method for comparing cellular profiles with higher weights on functional features of interest. In this pan-cancer application, we compare \~{}600 cell lines and \~{}8,000 tumor samples of 24 cancer types, using weights to emphasize known oncogenic alterations. We characterize the similarity of cell lines and tumors within and across cancers by using multiple datum types and rank cell lines by their inferred quality as representative models. Beyond the assessment of cell lines, the weighted similarity approach is adaptable to patient stratification in clinical trials and personalized medicine.},
	issn = {2667-2375},
	doi = {10.1016/j.crmeth.2021.100039},
	author = {Sinha, Rileen and Luna, Augustin and Schultz, Nikolaus and Sander, Chris}
}
@article {1628703,
	title = {CARM1 Inhibition Enables Immunotherapy of Resistant Tumors by Dual Action on Tumor Cells and T Cells},
	journal = {Cancer Discov},
	volume = {11},
	number = {8},
	year = {2021},
	month = {2021 Aug},
	pages = {2050-2071},
	abstract = {A number of cancer drugs activate innate immune pathways in tumor cells but unfortunately also compromise antitumor immune function. We discovered that inhibition of CARM1, an epigenetic enzyme and cotranscriptional activator, elicited beneficial antitumor activity in both cytotoxic T cells and tumor cells. In T cells, Carm1 inactivation substantially enhanced their antitumor function and preserved memory-like populations required for sustained antitumor immunity. In tumor cells, Carm1 inactivation induced a potent type 1 interferon response that sensitized resistant tumors to cytotoxic T cells. Substantially increased numbers of dendritic cells, CD8 T cells, and natural killer cells were present in Carm1-deficient tumors, and infiltrating CD8 T cells expressed low levels of exhaustion markers. Targeting of CARM1 with a small molecule elicited potent antitumor immunity and sensitized resistant tumors to checkpoint blockade. Targeting of this cotranscriptional regulator thus offers an opportunity to enhance immune function while simultaneously sensitizing resistant tumor cells to immune attack. SIGNIFICANCE: Resistance to cancer immunotherapy remains a major challenge. Targeting of CARM1 enables immunotherapy of resistant tumors by enhancing T-cell functionality and preserving memory-like T-cell populations within tumors. CARM1 inhibition also sensitizes resistant tumor cells to immune attack by inducing a tumor cell-intrinsic type 1 interferon response.This article is highlighted in the In This Issue feature, p. 1861.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-20-1144},
	author = {Kumar, Sushil and Zeng, Zexian and Bagati, Archis and Tay, Rong En and Sanz, Lionel A and Hartono, Stella R and Ito, Yoshinaga and Abderazzaq, Fieda and Hatchi, Elodie and Jiang, Peng and Cartwright, Adam N R and Olawoyin, Olamide and Mathewson, Nathan D and Pyrdol, Jason W and Li, Mamie Z and Doench, John G and Booker, Matthew A and Tolstorukov, Michael Y and Elledge, Stephen J and Ch{\'e}din, Fr{\'e}d{\'e}ric and Liu, X Shirley and Wucherpfennig, Kai W}
}
@article {1628708,
	title = {Cobomarsen, an Oligonucleotide Inhibitor of miR-155, Slows DLBCL Tumor Cell Growth and},
	journal = {Clin Cancer Res},
	volume = {27},
	number = {4},
	year = {2021},
	month = {2021 02 15},
	pages = {1139-1149},
	abstract = {PURPOSE: miRNA-155 is an oncogenic miRNA highly expressed in B-cell malignancies, particularly in the non-germinal center B-cell or activated B-cell subtype of diffuse large B-cell lymphoma (ABC-DLBCL), where it is considered a potential diagnostic and prognostic biomarker. Thus, miR-155 inhibition represents an important therapeutic strategy for B-cell lymphomas. In this study, we tested the efficacy and pharmacodynamic activity of an oligonucleotide inhibitor of miR-155, cobomarsen, in ABC-DLBCL cell lines and in corresponding xenograft mouse models. In addition, we assessed the therapeutic efficacy and safety of cobomarsen in a patient diagnosed with aggressive ABC-DLBCL. EXPERIMENTAL DESIGN: Preclinical studies included the delivery of cobomarsen to highly miR-155-expressing ABC-DLBCL cell lines to assess any phenotypic changes, as well as intravenous injections of cobomarsen in NSG mice carrying ABC-DLBCL xenografts, to study tumor growth and pharmacodynamics of the compound over time. To begin to test its safety and therapeutic efficacy, a patient was recruited who underwent five cycles of cobomarsen treatment. RESULTS: Cobomarsen decreased cell proliferation and induced apoptosis in ABC-DLBCL cell lines. Intravenous administration of cobomarsen in a xenograft NSG mouse model of ABC-DLBCL reduced tumor volume, triggered apoptosis, and derepressed direct miR-155 target genes. Finally, the compound reduced and stabilized tumor growth without any toxic effects for the patient. CONCLUSIONS: Our findings support the potential therapeutic application of cobomarsen in ABC-DLBCL and other types of lymphoma with elevated miR-155 expression.},
	keywords = {Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Female, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, MicroRNAs, Oligonucleotides, Antisense, Xenograft Model Antitumor Assays},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-20-3139},
	author = {Anastasiadou, Eleni and Seto, Anita G and Beatty, Xuan and Hermreck, Melanie and Gilles, Maud-Emmanuelle and Stroopinsky, Dina and Pinter-Brown, Lauren C and Pestano, Linda and Marchese, Cinzia and Avigan, David and Trivedi, Pankaj and Escolar, Diana M and Jackson, Aimee L and Slack, Frank J}
}
@article {1628692,
	title = {Dendritic cell paucity in mismatch repair-proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy},
	journal = {Proc Natl Acad Sci U S A},
	volume = {118},
	number = {45},
	year = {2021},
	month = {2021 11 09},
	abstract = {Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair-proficient (pMMR) CRCs make up about 95\% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.},
	keywords = {Animals, Cell Line, Tumor, Colorectal Neoplasms, Dendritic Cells, DNA Mismatch Repair, Drug Screening Assays, Antitumor, Humans, Immune Checkpoint Inhibitors, Interferon-gamma, Liver Neoplasms, Experimental, Male, Mice, Inbred C57BL},
	issn = {1091-6490},
	doi = {10.1073/pnas.2105323118},
	author = {Ho, William W and Gomes-Santos, Igor L and Aoki, Shuichi and Datta, Meenal and Kawaguchi, Kosuke and Talele, Nilesh P and Roberge, Sylvie and Ren, Jun and Liu, Hao and Chen, Ivy X and Andersson, Patrik and Chatterjee, Sampurna and Kumar, Ashwin S and Amoozgar, Zohreh and Zhang, Qixian and Huang, Peigen and Ng, Mei Rosa and Chauhan, Vikash P and Xu, Lei and Duda, Dan G and Clark, Jeffrey W and Pittet, Mikael J and Fukumura, Dai and Jain, Rakesh K}
}
@article {1628706,
	title = {An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence},
	journal = {Cancer Cell},
	volume = {39},
	number = {2},
	year = {2021},
	month = {2021 02 08},
	pages = {240-256.e11},
	abstract = {Treatment-persistent residual tumors impede curative cancer therapy. To understand this cancer cell state we generated models of treatment persistence that simulate the residual tumors. We observe that treatment-persistent tumor cells in organoids, xenografts, and cancer patients adopt a distinct and reversible transcriptional program resembling that of embryonic diapause, a dormant stage of suspended development triggered by stress and associated with suppressed Myc activity and overall biosynthesis. In cancer cells, depleting Myc or inhibiting Brd4, a Myc transcriptional co-activator, attenuates drug cytotoxicity through a dormant diapause-like adaptation with reduced apoptotic priming. Conversely, inducible Myc upregulation enhances acute chemotherapeutic activity. Maintaining residual cells in dormancy after chemotherapy by inhibiting Myc activity or interfering with the diapause-like adaptation by inhibiting cyclin-dependent kinase 9 represent potential therapeutic strategies against chemotherapy-persistent tumor cells. Our study demonstrates that cancer co-opts a mechanism similar to diapause with adaptive inactivation of Myc to persist during treatment.},
	keywords = {Adaptation, Physiological, Animals, Antineoplastic Agents, Apoptosis, Cell Line, Cell Line, Tumor, Cyclin-Dependent Kinase 9, Diapause, Embryo, Mammalian, Female, HEK293 Cells, Humans, MCF-7 Cells, Mice, Proto-Oncogene Proteins c-myc, Transcription Factors, Transcription, Genetic, Up-Regulation},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2020.12.002},
	author = {Dhimolea, Eugen and Simoes, Ricardo De Matos and Kansara, Dhvanir and Al{\textquoteright}Khafaji, Aziz and Bouyssou, Juliette and Weng, Xiang and Sharma, Shruti and Raja, Joseline and Awate, Pallavi and Shirasaki, Ryosuke and Tang, Huihui and Glassner, Brian J and Liu, Zhiyi and Gao, Dong and Bryan, Jordan and Bender, Samantha and Roth, Jennifer and Scheffer, Michal and Jeselsohn, Rinath and Gray, Nathanael S and Georgakoudi, Irene and Vazquez, Francisca and Tsherniak, Aviad and Chen, Yu and Welm, Alana and Duy, Cihangir and Melnick, Ari and Bartholdy, Boris and Brown, Myles and Culhane, Aedin C and Mitsiades, Constantine S}
}
@article {1628688,
	title = {Empirical identification and validation of tumor-targeting T cell receptors from circulation using autologous pancreatic tumor organoids},
	journal = {J Immunother Cancer},
	volume = {9},
	number = {11},
	year = {2021},
	month = {2021 11},
	abstract = {BACKGROUND: Tumor-specific cytotoxic T cells and T cell receptors are effective tools for cancer immunotherapy. Most efforts to identify them rely on known antigens or lymphocytes that have infiltrated into the tumor bed. Approaches to empirically identify tumor-targeting T cells and T cell receptors by exploiting all antigens expressed on tumor cell surfaces are not well developed for most carcinomas, including pancreatic cancer. METHODS: Autologous tumor organoids were stimulated with T cells from the patients{\textquoteright} peripheral blood for 2 weeks to generate the organoid-primed T (opT) cells. opT cell phenotype was analyzed by monitoring changes in the expression levels of 28 cell surface and checkpoint proteins. Expression of ligands of the immune checkpoints was investigated by immunohistochemistry staining. T cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) and assayed by flow cytometry to monitor tumor-induced T cell proliferation changes. opT cell-mediated killing of three-dimensional organoids was measured using an M30 ELISA kit. T cell receptors (TCRs) were identified by deep sequencing of gDNA isolated from T cells, and the TCR specificity was confirmed by transferring TCRs to the T cell line SKW-3 or donor T cells. RESULTS: The co-culture was effective in the generation of CD8 + or CD4+opT cells. The opT cells killed autologous tumors in a granzyme B or Fas-Fas ligand-dependent manner and expressed markers of tissue-resident memory phenotype. Each patient-derived opT cell culture displayed a unique complement of checkpoint proteins. Interestingly, only NKG2A blockade showed a potent increase in the interferon-γ production compared with blocking programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) or TIM3 or TIGIT or LAG3. Importantly, TCR sequencing demonstrated a dramatic clonal expansion of T cells with a restricted subset of TCRs. Cloning and transferring the TCRs to heterologous T cells was sufficient to confer tumor cell recognition and cytotoxic properties in a patient-specific manner. CONCLUSION: We report a platform for expanding tumor-targeting T cells from the peripheral blood of patients with pancreatic cancer. We identify the NKG2A-HLA-E axis as a potentially important checkpoint for CD8 +T cells for pancreatic cancer. Lastly, we demonstrate empirical identification of tumor-targeting TCRs that can be used for TCR-therapeutics.},
	keywords = {Animals, Humans, Mice, Organoids, Pancreatic Neoplasms, Receptors, Antigen, T-Cell},
	issn = {2051-1426},
	doi = {10.1136/jitc-2021-003213},
	author = {Meng, Qingda and Xie, Shanshan and Gray, G Kenneth and Dezfulian, Mohammad H and Li, Weilin and Huang, Ling and Akshinthala, Dipikaa and Ferrer, Elizabeth and Conahan, Catherine and Del Pino, Sofia Perea and Grossman, Joseph and Elledge, Stephen J and Hidalgo, Manuel and Muthuswamy, Senthil K}
}
@article {1628700,
	title = {Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity},
	journal = {Nature},
	volume = {595},
	number = {7866},
	year = {2021},
	month = {2021 07},
	pages = {309-314},
	abstract = {Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3-5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.},
	keywords = {Animals, Antigens, Viral, Chromatin, CRISPR-Cas Systems, Disease Models, Animal, DNA Transposable Elements, Female, Gene Silencing, Histocompatibility Antigens Class I, Histone-Lysine N-Methyltransferase, Humans, Mice, Neoplasms, Programmed Cell Death 1 Receptor, T-Lymphocytes, Cytotoxic},
	issn = {1476-4687},
	doi = {10.1038/s41586-021-03520-4},
	author = {Griffin, Gabriel K and Wu, Jingyi and Iracheta-Vellve, Arvin and Patti, James C and Hsu, Jeffrey and Davis, Thomas and Dele-Oni, Deborah and Du, Peter P and Halawi, Aya G and Ishizuka, Jeffrey J and Kim, Sarah Y and Klaeger, Susan and Knudsen, Nelson H and Miller, Brian C and Nguyen, Tung H and Olander, Kira E and Papanastasiou, Malvina and Rachimi, Suzanna and Robitschek, Emily J and Schneider, Emily M and Yeary, Mitchell D and Zimmer, Margaret D and Jaffe, Jacob D and Carr, Steven A and Doench, John G and Haining, W Nicholas and Yates, Kathleen B and Manguso, Robert T and Bernstein, Bradley E}
}
@article {1628701,
	title = {Exercise Training Improves Tumor Control by Increasing CD8 T-cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade},
	journal = {Cancer Immunol Res},
	volume = {9},
	number = {7},
	year = {2021},
	month = {2021 07},
	pages = {765-778},
	abstract = {The mechanisms behind the antitumor effects of exercise training (ExTr) are not fully understood. Using mouse models of established breast cancer, we examined here the causal role of CD8+ T cells in the benefit acquired from ExTr in tumor control, as well as the ability of ExTr to improve immunotherapy responses. We implanted E0771, EMT6, MMTV-PyMT, and MCa-M3C breast cancer cells orthotopically in wild-type or Cxcr3-/- female mice and initiated intensity-controlled ExTr sessions when tumors reached approximately 100 mm3 We characterized the tumor microenvironment (TME) using flow cytometry, transcriptome analysis, proteome array, ELISA, and immunohistochemistry. We used antibodies against CD8+ T cells for cell depletion. Treatment with immune checkpoint blockade (ICB) consisted of anti-PD-1 alone or in combination with anti-CTLA-4. ExTr delayed tumor growth and induced vessel normalization, demonstrated by increased pericyte coverage and perfusion and by decreased hypoxia. ExTr boosted CD8+ T-cell infiltration, with enhanced effector function. CD8+ T-cell depletion prevented the antitumor effect of ExTr. The recruitment of CD8+ T cells and the antitumor effects of ExTr were abrogated in Cxcr3-/- mice, supporting the causal role of the CXCL9/CXCL11-CXCR3 pathway. ExTr also sensitized ICB-refractory breast cancers to treatment. Our results indicate that ExTr can normalize the tumor vasculature, reprogram the immune TME, and enhance the antitumor activity mediated by CD8+ T cells via CXCR3, boosting ICB responses. Our findings and mechanistic insights provide a rationale for the clinical translation of ExTr to improve immunotherapy of breast cancer.},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-20-0499},
	author = {Gomes-Santos, Igor L and Amoozgar, Zohreh and Kumar, Ashwin S and Ho, William W and Roh, Kangsan and Talele, Nilesh P and Curtis, Hannah and Kawaguchi, Kosuke and Jain, Rakesh K and Fukumura, Dai}
}
@article {1628691,
	title = {FGFR-inhibitor-mediated dismissal of SWI/SNF complexes from YAP-dependent enhancers induces adaptive therapeutic resistance},
	journal = {Nat Cell Biol},
	volume = {23},
	number = {11},
	year = {2021},
	month = {2021 11},
	pages = {1187-1198},
	abstract = {How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodelling, leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters, resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenograft models. Collectively, these findings reveal a feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provides potential therapeutic strategies to overcome this mechanism of resistance.},
	keywords = {Amino Acids, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, DNA Helicases, Drug Resistance, Neoplasm, Drug Synergism, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Humans, Mechanistic Target of Rapamycin Complex 1, Molecular Targeted Therapy, Multiprotein Complexes, Nuclear Proteins, Phenylurea Compounds, Pyrimidines, Receptors, Fibroblast Growth Factor, Signal Transduction, Transcription Factors, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays, YAP-Signaling Proteins},
	issn = {1476-4679},
	doi = {10.1038/s41556-021-00781-z},
	author = {Li, Yihao and Qiu, Xintao and Wang, Xiaoqing and Liu, Hui and Renee C Geck and Tewari, Alok K and Xiao, Tengfei and Font-Tello, Alba and Lim, Klothilda and Jones, Kristen L and Morrow, Murry and Vadhi, Raga and Kao, Pei-Lun and Jaber, Aliya and Yerrum, Smitha and Xie, Yingtian and Chow, Kin-Hoe and Cejas, Paloma and Nguyen, Quang-D{\'e} and Long, Henry W and Liu, X Shirley and Toker, Alex and Brown, Myles}
}
@article {1628687,
	title = {The fission yeast FLCN/FNIP complex augments TORC1 repression or activation in response to amino acid (AA) availability},
	journal = {iScience},
	volume = {24},
	number = {11},
	year = {2021},
	month = {2021 Nov 19},
	pages = {103338},
	abstract = {The target of Rapamycin complex1 (TORC1) senses and integrates several environmental signals, including amino acid (AA) availability, to regulate cell growth. Folliculin (FLCN) is a tumor suppressor (TS) protein in renal cell carcinoma, which paradoxically activates TORC1 in response to AA supplementation. Few tractable systems for modeling FLCN as a TS are available. Here, we characterize the FLCN-containing complex in Schizosaccharomyces pombe (called BFC) and show that BFC augments TORC1 repression and activation in response to AA starvation and supplementation, respectively. BFC co-immunoprecipitates V-ATPase, a TORC1 modulator, and regulates its activity in an AA-dependent manner. BFC genetic and proteomic networks identify the conserved peptide transmembrane transporter Ptr2 and the phosphoribosylformylglycinamidine synthase Ade3 as new AA-dependent regulators of TORC1. Overall, these data ascribe an additional repressive function to Folliculin in TORC1 regulation and reveal S.\&nbsp;pombe as an excellent system for modeling the AA-dependent, FLCN-mediated repression of TORC1 in eukaryotes.},
	issn = {2589-0042},
	doi = {10.1016/j.isci.2021.103338},
	author = {Calvo, Isabel A and Sharma, Shalini and Paulo, Joao A and Gulka, Alexander O D and Boeszoermenyi, Andras and Zhang, Jingyu and Lombana, Jose M and Palmieri, Christina M and Laviolette, Laura A and Arthanari, Haribabu and Iliopoulos, Othon and Gygi, Steven P and Motamedi, Mo}
}
@article {1628707,
	title = {Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins},
	journal = {Cell Rep},
	volume = {34},
	number = {1},
	year = {2021},
	month = {2021 01 05},
	pages = {108532},
	abstract = {Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.},
	keywords = {Adaptor Proteins, Signal Transducing, Animals, Antineoplastic Agents, Cell Line, Tumor, CRISPR-Cas Systems, Cyclin-Dependent Kinase 9, Drug Resistance, Neoplasm, Gene Editing, Gene Expression Regulation, Neoplastic, Genes, Overlapping, Genome-Wide Association Study, Genomics, Humans, Mice, Multiple Myeloma, Oncogene Proteins, Proteins, Proteolysis, Tumor Cells, Cultured, Ubiquitin-Protein Ligases, Von Hippel-Lindau Tumor Suppressor Protein},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2020.108532},
	author = {Shirasaki, Ryosuke and Matthews, Geoffrey M and Gandolfi, Sara and Simoes, Ricardo De Matos and Buckley, Dennis L and Raja Vora, Joseline and Sievers, Quinlan L and Br{\"u}ggenthies, Johanna B and Dashevsky, Olga and Poarch, Haley and Tang, Huihui and Bariteau, Megan A and Sheffer, Michal and Hu, Yiguo and Downey-Kopyscinski, Sondra L and Hengeveld, Paul J and Glassner, Brian J and Dhimolea, Eugen and Ott, Christopher J and Zhang, Tinghu and Kwiatkowski, Nicholas P and Laubach, Jacob P and Schlossman, Robert L and Richardson, Paul G and Culhane, Aedin C and Groen, Richard W J and Fischer, Eric S and Vazquez, Francisca and Tsherniak, Aviad and Hahn, William C and Levy, Joan and Auclair, Daniel and Licht, Jonathan D and Keats, Jonathan J and Boise, Lawrence H and Ebert, Benjamin L and Bradner, James E and Gray, Nathanael S and Mitsiades, Constantine S}
}
@article {1628705,
	title = {Heterogeneity and Clonal Evolution of Acquired PARP Inhibitor Resistance in and -Deficient Cells},
	journal = {Cancer Res},
	volume = {81},
	number = {10},
	year = {2021},
	month = {2021 05 15},
	pages = {2774-2787},
	abstract = {Homologous recombination (HR)-deficient cancers are sensitive to poly-ADP ribose polymerase inhibitors (PARPi), which have shown clinical efficacy in the treatment of high-grade serous cancers (HGSC). However, the majority of patients will relapse, and acquired PARPi resistance is emerging as a pressing clinical problem. Here we generated seven single-cell clones with acquired PARPi resistance derived from a PARPi-sensitive TP53 -/- and BRCA1 -/- epithelial cell line generated using CRISPR/Cas9. These clones showed diverse resistance mechanisms, and some clones presented with multiple mechanisms of resistance at the same time. Genomic analysis of the clones revealed unique transcriptional and mutational profiles and increased genomic instability in comparison with a PARPi-sensitive cell line. Clonal evolutionary analyses suggested that acquired PARPi resistance arose via clonal selection from an intrinsically unstable and heterogenous cell population in the sensitive cell line, which contained preexisting drug-tolerant cells. Similarly, clonal and spatial heterogeneity in tumor biopsies from a clinical patient with BRCA1-mutant HGSC with acquired PARPi resistance was observed. In an imaging-based drug screening, the clones showed heterogenous responses to targeted therapeutic agents, indicating that not all PARPi-resistant clones can be targeted with just one therapy. Furthermore, PARPi-resistant clones showed mechanism-dependent vulnerabilities to the selected agents, demonstrating that a deeper understanding on the mechanisms of resistance could lead to improved targeting and biomarkers for HGSC with acquired PARPi resistance. SIGNIFICANCE: This study shows that BRCA1-deficient cells can give rise to multiple genomically and functionally heterogenous PARPi-resistant clones, which are associated with various vulnerabilities that can be targeted in a mechanism-specific manner.},
	keywords = {Animals, Apoptosis, BRCA1 Protein, Cell Proliferation, Clonal Evolution, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Genomic Instability, Homologous Recombination, Humans, Mice, Mice, Knockout, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Transcriptome, Tumor Cells, Cultured, Tumor Suppressor Protein p53},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-20-2912},
	author = {F{\"a}rkkil{\"a}, Anniina and Rodr{\'\i}guez, Alfredo and Oikkonen, Jaana and Gulhan, Doga C and Nguyen, Huy and Dom{\'\i}nguez, Julieta and Ramos, Sandra and Mills, Caitlin E and P{\'e}rez-Villatoro, Fernando and Lazaro, Jean-Bernard and Zhou, Jia and Clairmont, Connor S and Moreau, Lisa A and Park, Peter J and Sorger, Peter K and Hautaniemi, Sampsa and Frias, Sara and D{\textquoteright}Andrea, Alan D}
}
@article {1628697,
	title = {Losartan prevents tumor-induced hearing loss and augments radiation efficacy in NF2 schwannoma rodent models},
	journal = {Sci Transl Med},
	volume = {13},
	number = {602},
	year = {2021},
	month = {2021 07 14},
	abstract = {Hearing loss is one of the most common symptoms of neurofibromatosis type 2 (NF2) caused by vestibular schwannomas (VSs). Fibrosis in the VS tumor microenvironment (TME) is associated with hearing loss in patients with NF2. We hypothesized that reducing the fibrosis using losartan, an FDA-approved antihypertensive drug that blocks fibrotic and inflammatory signaling, could improve hearing. Using NF2 mouse models, we found that losartan treatment normalized the TME by (i) reducing neuroinflammatory IL-6/STAT3 signaling and preventing hearing loss, (ii) normalizing tumor vasculature and alleviating neuro-edema, and (iii) increasing oxygen delivery and enhancing efficacy of radiation therapy. In preparation to translate these exciting findings into the clinic, we used patient samples and data and demonstrated that IL-6/STAT3 signaling inversely associated with hearing function, that elevated production of tumor-derived IL-6 was associated with reduced viability of cochlear sensory cells and neurons in ex vivo organotypic cochlear cultures, and that patients receiving angiotensin receptor blockers have no progression in VS-induced hearing loss compared with patients on other or no antihypertensives based on a retrospective analysis of patients with VS and hypertension. Our study provides the rationale and critical data for a prospective clinical trial of losartan in patients with VS.},
	keywords = {Animals, Hearing Loss, Humans, Losartan, Mice, Neurilemmoma, Neurofibromatosis 2, Prospective Studies, Retrospective Studies, Rodentia, Treatment Outcome, Tumor Microenvironment},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.abd4816},
	author = {Wu, Limeng and Vasilijic, Sasa and Sun, Yao and Chen, Jie and Landegger, Lukas D and Zhang, Yanling and Zhou, Wenjianlong and Ren, Jun and Early, Samuel and Yin, Zhenzhen and Ho, William W and Zhang, Na and Gao, Xing and Lee, Grace Y and Datta, Meenal and Sagers, Jessica E and Brown, Alyssa and Muzikansky, Alona and Stemmer-Rachamimov, Anat and Zhang, Luo and Plotkin, Scott R and Jain, Rakesh K and Stankovic, Konstantina M and Xu, Lei}
}
@article {1628699,
	title = {Metabolic perturbations sensitize triple-negative breast cancers to apoptosis induced by BH3 mimetics},
	journal = {Sci Signal},
	volume = {14},
	number = {686},
	year = {2021},
	month = {2021 06 08},
	abstract = {Cancer cells have differential metabolic dependencies compared to their nonmalignant counterparts. However, few metabolism-targeting compounds have been successful in clinical trials. Here, we investigated the metabolic vulnerabilities of triple-negative breast cancer (TNBC), particularly those metabolic perturbations that increased mitochondrial apoptotic priming and sensitivity to BH3 mimetics (drugs that antagonize antiapoptotic proteins). We used high-throughput dynamic BH3 profiling (HT-DBP) to screen a library of metabolism-perturbing small molecules, which revealed inhibitors of the enzyme nicotinamide phosphoribosyltransferase (NAMPT) as top candidates. In some TNBC cells but not in nonmalignant cells, NAMPT inhibitors increased overall apoptotic priming and induced dependencies on specific antiapoptotic BCL-2 family members. Treatment of TNBC cells with NAMPT inhibitors sensitized them to subsequent treatment with BH3 mimetics. The combination of a NAMPT inhibitor (FK866) and an MCL-1 antagonist (S63845) reduced tumor growth in a TNBC patient-derived xenograft model in vivo. We found that NAMPT inhibition reduced NAD+ concentrations below a critical threshold that resulted in depletion of adenine, which was the metabolic trigger that primed TNBC cells for apoptosis. These findings demonstrate a close interaction between metabolic and mitochondrial apoptotic signaling pathways and reveal that exploitation of a tumor-specific metabolic vulnerability can sensitize some TNBC to BH3 mimetics.},
	keywords = {Apoptosis, Apoptosis Regulatory Proteins, Cell Line, Tumor, Humans, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Proto-Oncogene Proteins c-bcl-2, Triple Negative Breast Neoplasms},
	issn = {1937-9145},
	doi = {10.1126/scisignal.abc7405},
	author = {Daniels, Veerle W and Zoeller, Jason J and van Gastel, Nick and McQueeney, Kelley E and Parvin, Salma and Potter, Danielle S and Fell, Geoffrey G and Ferreira, Vin{\'\i}cius G and Yilma, Binyam and Gupta, Rajat and Spetz, Johan and Bhola, Patrick D and Endress, Jennifer E and Harris, Isaac S and Carrilho, Emanuel and Sarosiek, Kristopher A and Scadden, David T and Brugge, Joan S and Letai, Anthony}
}
@article {1628693,
	title = {Molecular response to PARP1 inhibition in ovarian cancer cells as determined by mass spectrometry based proteomics},
	journal = {J Ovarian Res},
	volume = {14},
	number = {1},
	year = {2021},
	month = {2021 Oct 22},
	pages = {140},
	abstract = {BACKGROUND: Poly (ADP)-ribose polymerase (PARP) inhibitors have entered routine clinical practice for the treatment of high-grade serous ovarian cancer (HGSOC), yet the molecular mechanisms underlying treatment response to PARP1 inhibition (PARP1i) are not fully understood. METHODS: Here, we used unbiased mass spectrometry based proteomics with data-driven protein network analysis to systematically characterize how HGSOC cells respond to PARP1i treatment. RESULTS: We found that PARP1i leads to pronounced proteomic changes in a diverse set of cellular processes in HGSOC cancer cells, consistent with transcript changes in an independent perturbation dataset. We interpret decreases in the levels of the pro-proliferative transcription factors SP1 and β-catenin and in growth factor signaling as reflecting the anti-proliferative effect of PARP1i; and the strong activation of pro-survival processes NF-κB signaling and lipid metabolism as PARPi-induced adaptive resistance mechanisms. Based on these observations, we nominate several protein targets for therapeutic inhibition in combination with PARP1i. When tested experimentally, the combination of PARPi with an inhibitor of fatty acid synthase (TVB-2640) has a 3-fold synergistic effect and is therefore of particular pre-clinical interest. CONCLUSION: Our study improves the current understanding of PARP1 function, highlights the potential that the anti-tumor efficacy of PARP1i may not only rely on DNA damage repair mechanisms and informs on the rational design of PARP1i combination therapies in ovarian cancer.},
	issn = {1757-2215},
	doi = {10.1186/s13048-021-00886-x},
	author = {Franz, Alexandra and Coscia, Fabian and Shen, Ciyue and Charaoui, Lea and Mann, Matthias and Sander, Chris}
}
@article {1628690,
	title = {Narrative online guides for the interpretation of digital-pathology images and tissue-atlas data},
	journal = {Nat Biomed Eng},
	year = {2021},
	month = {2021 Nov 08},
	abstract = {Multiplexed tissue imaging facilitates the diagnosis and understanding of complex disease traits. However, the analysis of such digital images heavily relies on the experience of anatomical pathologists for the review, annotation and description of tissue features. In addition, the wider use of data from tissue atlases in basic and translational research and in classrooms would benefit from software that facilitates the easy visualization and sharing of the images and the results of their analyses. In this Perspective, we describe the ecosystem of software available for the analysis of tissue images and discuss the need for interactive online guides that help histopathologists make complex images comprehensible to non-specialists. We illustrate this idea via a software interface (Minerva), accessible via web browsers, that integrates multi-omic and tissue-atlas features. We argue that such interactive narrative guides can effectively disseminate digital histology data and aid their interpretation.},
	issn = {2157-846X},
	doi = {10.1038/s41551-021-00789-8},
	author = {Rashid, Rumana and Chen, Yu-An and Hoffer, John and Muhlich, Jeremy L and Lin, Jia-Ren and Krueger, Robert and Hanspeter Pfister and Mitchell, Richard and Santagata, Sandro and Sorger, Peter K}
}
@article {1628704,
	title = {p53 dynamics vary between tissues and are linked with radiation sensitivity},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 02 09},
	pages = {898},
	abstract = {Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.},
	keywords = {Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Survival, Humans, Mice, Neoplasms, Protein Binding, Proto-Oncogene Proteins c-mdm2, Radiation Tolerance, Tissue Distribution, Tumor Burden, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-21145-z},
	author = {Stewart-Ornstein, Jacob and Iwamoto, Yoshiko and Miller, Miles A and Prytyskach, Mark A and Ferretti, Stephane and Holzer, Philipp and Kallen, Joerg and Furet, Pascal and Jambhekar, Ashwini and Forrester, William C and Weissleder, Ralph and Lahav, Galit}
}
@article {1628710,
	title = {Pleiotropic Mechanisms Drive Endocrine Resistance in the Three-Dimensional Bone Microenvironment},
	journal = {Cancer Res},
	volume = {81},
	number = {2},
	year = {2021},
	month = {2021 01 15},
	pages = {371-383},
	abstract = {Although hormonal therapy (HT) inhibits the growth of hormone receptor-positive (HR+) breast and prostate cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ breast cancer and prostate cancer spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of breast cancer and prostate cancer spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL6 or JAK signaling. Paracrine IL6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non-IL6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches. SIGNIFICANCE: This study uncovers a previously underappreciated dependency of tumor cells on HR signaling for anchorage-independent growth and highlights how the metastatic microenvironment restores this malignant property of cancer cells during hormone therapy.},
	keywords = {Animals, Antineoplastic Agents, Hormonal, Apoptosis, Biomarkers, Tumor, Bone Neoplasms, Breast Neoplasms, Cell Proliferation, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Male, Mice, Mice, Nude, Prostatic Neoplasms, Receptors, Estrogen, Tumor Cells, Cultured, Tumor Microenvironment, Xenograft Model Antitumor Assays},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-20-0571},
	author = {Dhimolea, Eugen and Simoes, Ricardo De Matos and Kansara, Dhvanir and Weng, Xiang and Sharma, Shruti and Awate, Pallavi and Liu, Zhiyi and Gao, Dong and Mitsiades, Nicholas and Schwab, Joseph H and Chen, Yu and Jeselsohn, Rinath and Culhane, Aed{\'\i}n C and Brown, Myles and Georgakoudi, Irene and Mitsiades, Constantine S}
}
@article {1628689,
	title = {Radiation combines with immune checkpoint blockade to enhance T cell priming in a murine model of poorly immunogenic pancreatic cancer},
	journal = {Open Biol},
	volume = {11},
	number = {11},
	year = {2021},
	month = {2021 11},
	pages = {210245},
	abstract = {Radiation has been a pillar of cancer therapy for decades. The effects of radiation on the anti-tumour immune response are variable across studies and have not been explicitly defined in poorly immunogenic tumour types. Here, we employed combination checkpoint blockade immunotherapy with stereotactic body radiation therapy and examined the effect on tumour growth and immune infiltrates in subcutaneous and orthotopic mouse models of pancreatic cancer. Although immune checkpoint blockade and radiation were ineffective alone, their combination produced a modest growth delay in both irradiated and non-irradiated tumours that corresponded with significant increases in CD8+ T cells, CD4+ T cells and tumour-specific T cells as identified by IFNγ ELISpot. We conclude that radiation enhances priming of tumour-specific T cells in poorly immunogenic tumours and that the frequency of these T cells can be further increased by combination with immune checkpoint blockade.},
	issn = {2046-2441},
	doi = {10.1098/rsob.210245},
	author = {Stump, Courtney T and Roehle, Kevin and Manjarrez Orduno, Nataly and Dougan, Stephanie K}
}
@article {1628695,
	title = {Sex-Biased Mutations in Myeloid Malignancies Impair Plasmacytoid Dendritic Cell Activation and Apoptosis},
	journal = {Cancer Discov},
	year = {2021},
	month = {2021 Oct 06},
	abstract = {Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive leukemia of plasmacytoid dendritic cells (pDC). BPDCN occurs at least three times more frequently in men than in women, but the reasons for this sex bias are unknown. Here, studying genomics of primary BPDCN and modeling disease-associated mutations, we link acquired alterations in RNA splicing to abnormal pDC development and inflammatory response through Toll-like receptors. Loss-of-function mutations in ZRSR2, an X chromosome gene encoding a splicing factor, are enriched in BPDCN, and nearly all mutations occur in males. ZRSR2 mutation impairs pDC activation and apoptosis after inflammatory stimuli, associated with intron retention and inability to upregulate the transcription factor IRF7. In vivo, BPDCN-associated mutations promote pDC expansion and signatures of decreased activation. These data support a model in which male-biased mutations in hematopoietic progenitors alter pDC function and confer protection from apoptosis, which may impair immunity and predispose to leukemic transformation. SIGNIFICANCE: Sex bias in cancer is well recognized, but the underlying mechanisms are incompletely defined. We connect X chromosome mutations in ZRSR2 to an extremely male-predominant leukemia. Aberrant RNA splicing induced by ZRSR2 mutation impairs dendritic cell inflammatory signaling, interferon production, and apoptosis, revealing a sex- and lineage-related tumor suppressor pathway.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-20-1513},
	author = {Togami, Katsuhiro and Chung, Sun Sook and Madan, Vikas and Booth, Christopher A G and Kenyon, Christopher M and Cabal-Hierro, Lucia and Taylor, Justin and Kim, Sunhee S and Griffin, Gabriel K and Ghandi, Mahmoud and Li, Jia and Li, Yvonne Y and Angelot-Delettre, Fanny and Biichle, Sabeha and Seiler, Michael and Buonamici, Silvia and Lovitch, Scott B and Louissaint, Abner and Morgan, Elizabeth A and Jardin, Fabrice and Piccaluga, Pier Paolo and Weinstock, David M and Hammerman, Peter S and Yang, Henry and Konopleva, Marina and Pemmaraju, Naveen and Garnache-Ottou, Francine and Abdel-Wahab, Omar and Koeffler, H Phillip and Lane, Andrew A}
}
@article {1628696,
	title = {Systematic tissue collection during clinical breast biopsy is feasible, safe and enables high-content translational analyses},
	journal = {NPJ Precis Oncol},
	volume = {5},
	number = {1},
	year = {2021},
	month = {2021 Sep 21},
	pages = {85},
	abstract = {Systematic collection of fresh tissues for research at the time of diagnostic image-guided breast biopsy has the potential to fuel a wide variety of innovative studies. Here we report the initial experience, including safety, feasibility, and laboratory proof-of-principle, with the collection and analysis of research specimens obtained via breast core needle biopsy immediately following routine clinical biopsy at a single institution over a 14-month period. Patients underwent one or two additional core biopsies following collection of all necessary clinical specimens. In total, 395 patients were approached and 270 consented to the research study, yielding a 68.4\% consent rate. Among consenting patients, 238 lesions were biopsied for research, resulting in 446 research specimens collected. No immediate complications were observed. Representative research core specimens showed high diagnostic concordance with clinical core biopsies. Flow cytometry demonstrated consistent recovery of hundreds to thousands of viable cells per research core. Among a group of HER2 + tumor research specimens, HER2 assessment by flow cytometry correlated highly with immunohistochemistry (IHC) staining, and in addition revealed extensive inter- and intra-tumoral variation in HER2 levels of potential clinical relevance. Suitability for single-cell transcriptomic analysis was demonstrated for a triple-negative tumor core biopsy, revealing substantial cellular diversity in the tumor immune microenvironment, including a prognostically relevant T cell subpopulation. Thus, collection of fresh tissues for research purposes at the time of diagnostic breast biopsy is safe, feasible and efficient, and may provide a high-yield mechanism to generate a rich tissue repository for a wide variety of cross-disciplinary research.},
	issn = {2397-768X},
	doi = {10.1038/s41698-021-00224-w},
	author = {Koh, Siang-Boon and Dontchos, Brian N and Bossuyt, Veerle and Edmonds, Christine and Cristea, Simona and Melkonjan, Nsan and Mortensen, Lindsey and Ma, Annie and Beyerlin, Kassidy and Denault, Elyssa and Niehoff, Elizabeth and Hirz, Taghreed and Sykes, David B and Michor, Franziska and Specht, Michelle and Lehman, Constance and Ellisen, Leif W and Spring, Laura M}
}
@article {1628694,
	title = {Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms},
	journal = {Cancer Cell},
	volume = {39},
	number = {11},
	year = {2021},
	month = {2021 11 08},
	pages = {1531-1547.e10},
	abstract = {Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs{\textquoteright} functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient{\textquoteright}s tumor. We have established a living biobank of CAFs derived from biopsies of patients{\textquoteright} non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-β signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients{\textquoteright} clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.},
	keywords = {Biopsy, Cancer-Associated Fibroblasts, Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, Fibroblast Growth Factor 7, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor, Humans, Lung Neoplasms, Precision Medicine, Signal Transduction, Transforming Growth Factor beta, Tumor Microenvironment, Up-Regulation},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2021.09.003},
	author = {Hu, Haichuan and Piotrowska, Zofia and Hare, Patricia J and Chen, Huidong and Mulvey, Hillary E and Mayfield, Aislinn and Noeen, Sundus and Kattermann, Krystina and Greenberg, Max and Williams, August and Riley, Amanda K and Wilson, Jarad J and Mao, Ying-Qing and Huang, Ruo-Pan and Banwait, Mandeep K and Ho, Jeffrey and Crowther, Giovanna S and Hariri, Lida P and Heist, Rebecca S and Kodack, David P and Pinello, Luca and Shaw, Alice T and Mino-Kenudson, Mari and Hata, Aaron N and Sequist, Lecia V and Benes, Cyril H and Niederst, Matthew J and Engelman, Jeffrey A}
}
@article {1616323,
	title = {Best Practices for Spatial Profiling for Breast Cancer Research with the GeoMx Digital Spatial Profiler},
	journal = {Cancers (Basel)},
	volume = {13},
	number = {17},
	year = {2021},
	month = {2021 Sep 04},
	abstract = {Breast cancer is a heterogenous disease with variability in tumor cells and in the surrounding tumor microenvironment (TME). Understanding the molecular diversity in breast cancer is critical for improving prediction of therapeutic response and prognostication. High-plex spatial profiling of tumors enables characterization of heterogeneity in the breast TME, which can holistically illuminate the biology of tumor growth, dissemination and, ultimately, response to therapy. The GeoMx Digital Spatial Profiler (DSP) enables researchers to spatially resolve and quantify proteins and RNA transcripts from tissue sections. The platform is compatible with both formalin-fixed paraffin-embedded and frozen tissues. RNA profiling was developed at the whole transcriptome level for human and mouse samples and protein profiling of 100-plex for human samples. Tissue can be optically segmented for analysis of regions of interest or cell populations to study biology-directed tissue characterization. The GeoMx Breast Cancer Consortium (GBCC) is composed of breast cancer researchers who are developing innovative approaches for spatial profiling to accelerate biomarker discovery. Here, the GBCC presents best practices for GeoMx profiling to promote the collection of high-quality data, optimization of data analysis and integration of datasets to advance collaboration and meta-analyses. Although the capabilities of the platform are presented in the context of breast cancer research, they can be generalized to a variety of other tumor types that are characterized by high heterogeneity.},
	issn = {2072-6694},
	doi = {10.3390/cancers13174456},
	author = {Bergholtz, Helga and Carter, Jodi M and Cesano, Alessandra and Cheang, Maggie Chon U and Church, Sarah E and Divakar, Prajan and Fuhrman, Christopher A and Goel, Shom and Gong, Jingjing and Guerriero, Jennifer L and Hoang, Margaret L and Hwang, E Shelley and Kuasne, Hellen and Lee, Jinho and Liang, Yan and Mittendorf, Elizabeth A and Perez, Jessica and Prat, Aleix and Pusztai, Lajos and Reeves, Jason W and Riazalhosseini, Yasser and Richer, Jennifer K and Sahin, {\"O}zg{\"u}r and Sato, Hiromi and Schlam, Ilana and S{\o}rlie, Therese and Stover, Daniel G and Swain, Sandra M and Swarbrick, Alexander and Thompson, E Aubrey and Tolaney, Sara M and Warren, Sarah E and Warren, Sarah E}
}
@article {1616319,
	title = {Comparing syngeneic and autochthonous models of breast cancer to identify tumor immune components that correlate with response to immunotherapy in breast cancer},
	journal = {Breast Cancer Res},
	volume = {23},
	number = {1},
	year = {2021},
	month = {2021 08 05},
	pages = {83},
	abstract = {BACKGROUND: The heterogeneity of the breast tumor microenvironment (TME) may contribute to the lack of durable responses to immune checkpoint blockade (ICB); however, mouse models to test this are currently lacking. Proper selection and use of preclinical models are necessary for rigorous, preclinical studies to rapidly move laboratory findings into the clinic. METHODS: Three versions of a common syngeneic model derived from the MMTV-PyMT autochthonous model were generated by inoculating 1E6, 1E5, or 1E4 cells derived from the MMTV-PyMT mouse into wildtype recipient mice. To elucidate how tumor latency and TME heterogeneity contribute to ICB resistance, comprehensive characterization of the TME using quantitative flow-cytometry and RNA expression analysis (NanoString) was performed. Subsequently, response to ICB was tested. These procedures were repeated using the EMT6 breast cancer model. RESULTS: The 3 syngeneic versions of the MMTV-PyMT model had vastly different TMEs that correlated to ICB response. The number of cells used to generate syngeneic tumors significantly influenced tumor latency, infiltrating leukocyte populations, and response to ICB. These results were confirmed using the EMT6 breast cancer model. Compared to the MMTV-PyMT autochthonous model, all 3 MMTV-PyMT syngeneic models had significantly more tumor-infiltrating lymphocytes (TILs; CD3+, CD4+, and CD8+) and higher proportions of PD-L1-positive myeloid cells, whereas the MMTV-PyMT autochthonous model had the highest frequency of myeloid cells out of total leukocytes. Increased TILs correlated with response to anti-PD-L1 and anti-CTLA-4 therapy, but PD-L1expression on tumor cells or PD-1 expression of T cells did not. CONCLUSIONS: These studies reveal that tumor cell number correlates with tumor latency, TME, and response to ICB. ICB-sensitive and resistant syngeneic breast cancer models were identified, in which the 1E4 syngeneic model was most resistant to ICB. Given the lack of benefit from ICB in breast cancer, identifying robust murine models presented here provides the opportunity to further interrogate the TME for breast cancer treatment and provide novel insights into therapeutic combinations to overcome ICB resistance.},
	issn = {1465-542X},
	doi = {10.1186/s13058-021-01448-1},
	author = {Lal, Jessica Castrillon and Townsend, Madeline G and Mehta, Anita K and Oliwa, Madisson and Eric Miller and Sotayo, Alaba and Cheney, Emily and Mittendorf, Elizabeth A and Letai, Anthony and Guerriero, Jennifer L}
}
@article {1616320,
	title = {FcγR engagement reprograms neutrophils into antigen cross-presenting cells that elicit acquired anti-tumor immunity},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 08 09},
	pages = {4791},
	abstract = {Classical dendritic cells (cDC) are professional antigen-presenting cells (APC) that regulate immunity and tolerance. Neutrophil-derived cells with properties of DCs (nAPC) are observed in human diseases and after culture of neutrophils with cytokines. Here we show that FcγR-mediated endocytosis of antibody-antigen complexes or an anti-FcγRIIIB-antigen conjugate converts neutrophils into nAPCs that, in contrast to those generated with cytokines alone, activate T cells to levels observed with cDCs and elicit CD8+ T cell-dependent anti-tumor immunity\&nbsp;in mice. Single cell transcript analyses and validation studies implicate the transcription factor PU.1 in neutrophil to nAPC conversion. In humans, blood nAPC frequency in lupus patients correlates with disease. Moreover, anti-FcγRIIIB-antigen conjugate treatment induces nAPCs that can activate autologous T cells when using neutrophils from individuals with myeloid neoplasms that harbor neoantigens or those vaccinated against bacterial toxins. Thus, anti-FcγRIIIB-antigen conjugate-induced conversion of neutrophils to immunogenic nAPCs may represent a possible immunotherapy for cancer and infectious diseases.},
	keywords = {Adaptor Proteins, Vesicular Transport, Animals, Antigen Presentation, Antigen-Antibody Complex, Antigens, Neoplasm, Bone Marrow, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Movement, Cell Proliferation, Cytokines, Dendritic Cells, Endocytosis, Humans, Immunity, Innate, Immunotherapy, Lymph Nodes, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Neoplasms, Neutrophils, Reactive Oxygen Species, Receptors, IgG, Transcriptome},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-24591-x},
	author = {Mysore, Vijayashree and Cullere, Xavier and Mears, Joseph and Rosetti, Florencia and Okubo, Koshu and Liew, Pei X and Zhang, Fan and Madera-Salcedo, Iris and Rosenbauer, Frank and Stone, Richard M and Aster, Jon C and von Andrian, Ulrich H and Lichtman, Andrew H and Raychaudhuri, Soumya and Mayadas, Tanya N}
}
@article {1616321,
	title = {The MCF10 Model of Breast Tumor Progression},
	journal = {Cancer Res},
	volume = {81},
	number = {16},
	year = {2021},
	month = {2021 Aug 15},
	pages = {4183-4185},
	abstract = {The MCF10 cell lines first described by Soule and colleagues in 1990 have been a great resource for the breast cancer research community, facilitating research on the regulation of normal breast epithelial phenotypes and progressive changes in this regulation during malignancy. Here we review the development of the MCF10 parental and subsequent sublines and highlight a few of the major contributions of MCF10 model systems to breast cancer research.See related article by Soule and colleagues, Cancer Res 1990;50:6075-86.},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-21-1939},
	author = {Puleo, Julieann and Polyak, Kornelia}
}
@article {1616324,
	title = {Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 09 21},
	pages = {5563},
	abstract = {Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin {\textpm} pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95\% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.},
	keywords = {Adult, Aged, Antibodies, Monoclonal, Humanized, Antigen Presentation, Antineoplastic Combined Chemotherapy Protocols, B7-H1 Antigen, Breast Neoplasms, Cytokines, Drug Resistance, Neoplasm, Estrogens, Female, Furans, Gene Expression Profiling, Genetic Heterogeneity, Genome, Human, Genomics, Humans, Immune Checkpoint Inhibitors, Ketones, Lymphocytes, Tumor-Infiltrating, Male, Middle Aged, Mutation, Neoplasm Metastasis, Receptors, Estrogen, Receptors, Progesterone, Signal Transduction, Survival Rate, Treatment Outcome},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-25769-z},
	author = {Keenan, Tanya E and Guerriero, Jennifer L and Barroso-Sousa, Romualdo and Li, Tianyu and O{\textquoteright}Meara, Tess and Giobbie-Hurder, Anita and Tayob, Nabihah and Hu, Jiani and Severgnini, Mariano and Agudo, Judith and Vaz-Luis, Ines and Anderson, Leilani and Attaya, Victoria and Park, Jihye and Conway, Jake and He, Meng Xiao and Reardon, Brendan and Shannon, Erin and Wulf, Gerburg and Spring, Laura M and Jeselsohn, Rinath and Krop, Ian and Lin, Nancy U and Partridge, Ann and Winer, Eric P and Mittendorf, Elizabeth A and Liu, David and Van Allen, Eliezer M and Tolaney, Sara M}
}
@article {1616322,
	title = {Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer},
	journal = {Cancer Discov},
	volume = {11},
	number = {10},
	year = {2021},
	month = {2021 Oct},
	pages = {2436-2445},
	abstract = {Sacituzumab govitecan (SG), the first antibody-drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1 E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2 T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. SIGNIFICANCE: These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.This article is highlighted in the In This Issue feature, p. 2355.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-21-0702},
	author = {Coates, James T and Sun, Sheng and Leshchiner, Ignaty and Thimmiah, Nayana and Martin, Elizabeth E and McLoughlin, Daniel and Danysh, Brian P and Slowik, Kara and Jacobs, Raquel A and Rhrissorrakrai, Kahn and Utro, Filippo and Levovitz, Chaya and Denault, Elyssa and Walmsley, Charlotte S and Kambadakone, Avinash and Stone, James R and Isakoff, Steven J and Parida, Laxmi and Juric, Dejan and Getz, Gad and Bardia, Aditya and Ellisen, Leif W}
}
@article {1616325,
	title = {A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 09 22},
	pages = {5574},
	abstract = {In a trial of patients with high grade serous ovarian cancer (HGSOC), addition of the ATR inhibitor berzosertib to gemcitabine improved progression free survival (PFS) compared to gemcitabine alone but biomarkers predictive of treatment are lacking. Here we report a candidate biomarker of response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in HGSOC ovarian cancer. Patients with replication stress (RS)-high tumors (n = 27), defined as harboring at least one genomic RS alteration related to loss of RB pathway regulation and/or oncogene-induced replication stress achieve significantly prolonged PFS (HR = 0.38, 90\% CI, 0.17-0.86) on gemcitabine monotherapy compared to those with tumors without such alterations (defined as RS-low, n = 30). However, addition of berzosertib to gemcitabine benefits only patients with RS-low tumors (gemcitabine/berzosertib HR 0.34, 90\% CI, 0.13-0.86) and not patients with RS-high tumors (HR 1.11, 90\% CI, 0.47-2.62). Our findings support the notion that the exacerbation of RS by gemcitabine monotherapy is adequate for lethality in RS-high tumors. Conversely, for RS-low tumors addition of berzosertib-mediated ATR inhibition to gemcitabine is necessary for lethality to occur. Independent prospective validation of this biomarker is required.},
	keywords = {Antineoplastic Combined Chemotherapy Protocols, Ataxia Telangiectasia Mutated Proteins, Biomarkers, Tumor, Deoxycytidine, DNA Replication, Female, Humans, Isoxazoles, Mutation, Oncogenes, Ovarian Neoplasms, progression-free survival, Protein Kinase Inhibitors, Pyrazines, Recombinational DNA Repair, Retinoblastoma Binding Proteins},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-25904-w},
	author = {Konstantinopoulos, Panagiotis A and da Costa, Alexandre Andr{\'e} B A and Gulhan, Doga and Lee, Elizabeth K and Cheng, Su-Chun and Hendrickson, Andrea E Wahner and Kochupurakkal, Bose and Kolin, David L and Kohn, Elise C and Liu, Joyce F and Stover, Elizabeth H and Curtis, Jennifer and Tayob, Nabihah and Polak, Madeline and Chowdhury, Dipanjan and Matulonis, Ursula A and F{\"a}rkkil{\"a}, Anniina and D{\textquoteright}Andrea, Alan D and Shapiro, Geoffrey I}
}
@article {1616326,
	title = {Whole chromosome loss and genomic instability in mouse embryos after CRISPR-Cas9 genome editing},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 10 06},
	pages = {5855},
	abstract = {Karyotype alterations have emerged as on-target complications from CRISPR-Cas9 genome editing. However, the events that lead to these karyotypic changes in embryos after Cas9-treatment remain unknown. Here, using imaging and single-cell genome sequencing of 8-cell stage embryos, we track both spontaneous and Cas9-induced karyotype aberrations through the first three divisions of embryonic development. We observe the generation of abnormal structures of the nucleus that arise as a consequence of errors in mitosis, including micronuclei and chromosome bridges, and determine their contribution to common karyotype aberrations including whole chromosome loss that has been recently reported after editing in embryos. Together, these data demonstrate that Cas9-mediated germline genome editing can lead to unwanted on-target side effects, including major chromosome structural alterations that can be propagated over several divisions of embryonic development.},
	keywords = {Animals, Chromosome Segregation, Chromosome Structures, CRISPR-Cas Systems, Embryo, Mammalian, Embryonic Development, Gene Editing, Genomic Instability, Karyotype, Mice, Whole Genome Sequencing},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-26097-y},
	author = {Papathanasiou, Stamatis and Styliani Markoulaki and Blaine, Logan J and Leibowitz, Mitchell L and Zhang, Cheng-Zhong and Jaenisch, Rudolf and Pellman, David}
}
@article {1605440,
	title = {Cycling cancer persister cells arise from lineages with distinct programs},
	journal = {Nature},
	volume = {596},
	number = {7873},
	year = {2021},
	month = {2021 08},
	pages = {576-582},
	abstract = {Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell{\textquoteright}s clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with persister proliferative capacity across multiple cancer types. Impeding oxidative stress or metabolic reprogramming alters the fraction of cycling persisters. In human tumours, programs associated with cycling persisters are induced in minimal residual disease in response to multiple targeted therapies. The Watermelon system enabled the identification of rare persister lineages that are preferentially poised to proliferate under drug pressure, thus exposing new vulnerabilities that can be targeted to delay or even prevent disease recurrence.},
	keywords = {Antioxidants, Cell Cycle, Cell Line, Tumor, Cell Lineage, Cell Proliferation, Cell Survival, Clone Cells, DNA Barcoding, Taxonomic, Fatty Acids, Gene Expression Regulation, Neoplastic, Humans, Lentivirus, Neoplasm Recurrence, Local, Neoplasms, Oncogene Proteins, Oxidation-Reduction, Oxidative Stress, Reactive Oxygen Species, Transcription, Genetic},
	issn = {1476-4687},
	doi = {10.1038/s41586-021-03796-6},
	author = {Oren, Yaara and Tsabar, Michael and Cuoco, Michael S and Amir-Zilberstein, Liat and Cabanos, Heidie F and H{\"u}tter, Jan-Christian and Hu, Bomiao and Thakore, Pratiksha I and Tabaka, Marcin and Fulco, Charles P and Colgan, William and Cuevas, Brandon M and Hurvitz, Sara A and Slamon, Dennis J and Deik, Amy and Pierce, Kerry A and Clish, Clary and Hata, Aaron N and Zaganjor, Elma and Lahav, Galit and Politi, Katerina and Brugge, Joan S and Regev, Aviv}
}
@article {1603683,
	title = {cIAP1/2 antagonism eliminates MHC class I-negative tumors through T cell-dependent reprogramming of mononuclear phagocytes},
	journal = {Sci Transl Med},
	volume = {13},
	number = {594},
	year = {2021},
	month = {2021 05 19},
	abstract = {Loss of major histocompatibility complex (MHC) class I and interferon-γ (IFN-γ) sensing are major causes of primary and acquired resistance to checkpoint blockade immunotherapy. Thus, additional treatment options are needed for tumors that lose expression of MHC class I. The cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1/2) regulate classical and alternative nuclear factor κB (NF-κB) signaling. Induction of noncanonical NF-κB signaling with cIAP1/2 antagonists mimics costimulatory signaling, augmenting antitumor immunity. We show that induction of noncanonical NF-κB signaling induces T cell-dependent immune responses, even in β2-microglobulin (β2M)-deficient tumors, demonstrating that direct CD8 T cell recognition of tumor cell-expressed MHC class I is not required. Instead, T cell-produced lymphotoxin reprograms both mouse and human macrophages to be tumoricidal. In wild-type mice, but not mice incapable of antigen-specific T cell responses, cIAP1/2 antagonism reduces tumor burden by increasing phagocytosis of live tumor cells. Efficacy is augmented by combination with CD47 blockade. Thus, activation of noncanonical NF-κB stimulates a T cell-macrophage axis that curtails growth of tumors that are resistant to checkpoint blockade because of loss of MHC class I or IFN-γ sensing. These findings provide a potential mechanism for controlling checkpoint blockade refractory tumors.},
	keywords = {Animals, Cellular Reprogramming, Histocompatibility Antigens Class I, Humans, Immunotherapy, Inhibitor of Apoptosis Proteins, Interferon-gamma, Macrophages, Mice, Neoplasms, NF-kappa B, Phagocytes, Signal Transduction, T-Lymphocytes},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.abf5058},
	url = {https://pubmed.ncbi.nlm.nih.gov/34011631/},
	author = {Roehle, Kevin and Qiang, Li and Ventre, Katherine S and Heid, Daniel and Ali, Lestat R and Lenehan, Patrick and Heckler, Max and Crowley, Stephanie J and Stump, Courtney T and Ro, Gabrielle and Godicelj, An{\v z}e and Bhuiyan, Aladdin M and Yang, Annan and Quiles Del Rey, Maria and Biary, Tamara and Luoma, Adrienne M and Bruck, Patrick T and Tegethoff, Jana F and Nopper, Svenja L and Li, Jinyang and Byrne, Katelyn T and Pelletier, Marc and Wucherpfennig, Kai W and Stanger, Ben Z and Akin, James J and Mancias, Joseph D and Agudo, Judith and Dougan, Michael and Dougan, Stephanie K}
}
@article {1603679,
	title = {Cohesin mutations in myeloid malignancies},
	journal = {Blood},
	year = {2021},
	month = {2021 Jun 22},
	abstract = {Cohesin is a multi-subunit protein complex that forms a ring-like structure around DNA. Cohesin is essential for sister chromatid cohesion, chromatin organization, transcriptional regulation and DNA damage repair, and plays a major role in dynamically shaping the genome architecture and maintaining DNA integrity. The core complex subunits STAG2, RAD21, SMC1 and SMC3, as well as its modulators PDS5A/B, WAPL and NIPBL, have been found to be recurrently mutated in hematologic and solid malignancies. These mutations are found across the full spectrum of myeloid neoplasia, including pediatric Down Syndrome-associated acute megakaryoblastic leukemia (DS-AMKL), myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and de-novo and secondary acute myeloid leukemia (AML). The mechanisms by which cohesin mutations act as drivers of clonal expansion and disease progression are still poorly understood. Recent studies have described the impact of cohesin alterations on self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC), which are associated with changes in chromatin and epigenetic state directing lineage commitment, as well as genomic integrity. Here, we will review the role of the cohesin complex in healthy and malignant hematopoiesis. We will discuss clinical implications of cohesin mutations in myeloid malignancies and discuss opportunities for therapeutic targeting.},
	issn = {1528-0020},
	doi = {10.1182/blood.2019004259},
	author = {Jann, Joahnn-Christoph and Tothova, Zuzana}
}
@article {1603677,
	title = {FATTY ACID SYNTHESIS IS REQUIRED FOR BREAST CANCER BRAIN METASTASIS},
	journal = {Nat Cancer},
	volume = {2},
	number = {4},
	year = {2021},
	month = {2021 Apr},
	pages = {414-428},
	abstract = {Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.},
	issn = {2662-1347},
	doi = {10.1038/s43018-021-00183-y},
	author = {Ferraro, Gino B and Ali, Ahmed and Luengo, Alba and Kodack, David P and Deik, Amy and Abbott, Keene L and Bezwada, Divya and Blanc, Landry and Prideaux, Brendan and Jin, Xin and Possada, Jessica M and Chen, Jiang and Chin, Christopher R and Amoozgar, Zohreh and Ferreira, Raphael and Chen, Ivy and Naxerova, Kamila and Ng, Christopher and Westermark, Anna M and Duquette, Mark and Roberge, Sylvie and Lindeman, Neal I and Lyssiotis, Costas A and Nielsen, Jens and Housman, David E and Duda, Dan G and Brachtel, Elena and Golub, Todd R and Cantley, Lewis C and Asara, John M and Davidson, Shawn M and Fukumura, Dai and Dartois, V{\'e}ronique A and Clish, Clary B and Jain, Rakesh K and Vander Heiden, Matthew G}
}
@article {1603676,
	title = {A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors},
	journal = {Nat Cancer},
	volume = {2},
	number = {6},
	year = {2021},
	month = {2021 Jun},
	pages = {598-610},
	abstract = {DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in GEMM, xenograft and PDX models. Increased POLθ levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to PARP inhibitors (PARPi) are sensitive to NVB in vitro and in vivo. Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-strand DNA intermediates and non-functional RAD51 foci. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).},
	issn = {2662-1347},
	doi = {10.1038/s43018-021-00203-x},
	author = {Zhou, Jia and Gelot, Camille and Pantelidou, Constantia and Li, Adam and Y{\"u}cel, Hatice and Davis, Rachel E and Farkkila, Anniina and Kochupurakkal, Bose and Syed, Aleem and Shapiro, Geoffrey I and Tainer, John A and Blagg, Brian S J and Ceccaldi, Raphael and D{\textquoteright}Andrea, Alan D}
}
@article {1603675,
	title = {Genome-scale screens identify factors regulating tumor cell responses to natural killer cells},
	journal = {Nat Genet},
	volume = {53},
	number = {8},
	year = {2021},
	month = {2021 08},
	pages = {1196-1206},
	abstract = {To systematically define molecular features in human tumor cells that determine their degree of sensitivity to human allogeneic natural killer (NK) cells, we quantified the NK cell responsiveness of hundreds of molecularly annotated {\textquoteright}DNA-barcoded{\textquoteright} solid tumor cell lines in multiplexed format and applied genome-scale CRISPR-based gene-editing screens in several solid tumor cell lines, to functionally interrogate which genes in tumor cells regulate the response to NK cells. In these orthogonal studies, NK cell-sensitive tumor cells tend to exhibit {\textquoteright}mesenchymal-like{\textquoteright} transcriptional programs; high transcriptional signature for chromatin remodeling complexes; high levels of B7-H6 (NCR3LG1); and low levels of HLA-E/antigen presentation genes. Importantly, transcriptional signatures of NK cell-sensitive tumor cells correlate with immune checkpoint inhibitor (ICI) resistance in clinical samples. This study provides a comprehensive map of mechanisms regulating tumor cell responses to NK cells, with implications for future biomarker-driven applications of NK cell immunotherapies.},
	keywords = {Allogeneic Cells, Animals, B7 Antigens, Cell Line, Tumor, Chromatin Assembly and Disassembly, Cytotoxicity Tests, Immunologic, Cytotoxicity, Immunologic, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Genome, Human, Histocompatibility Antigens Class I, Humans, Immune Checkpoint Inhibitors, Killer Cells, Natural, Mice, Inbred NOD, Xenograft Model Antitumor Assays},
	issn = {1546-1718},
	doi = {10.1038/s41588-021-00889-w},
	author = {Sheffer, Michal and Lowry, Emily and Beelen, Nicky and Borah, Minasri and Amara, Suha Naffar-Abu and Mader, Chris C and Roth, Jennifer A and Tsherniak, Aviad and Freeman, Samuel S and Dashevsky, Olga and Gandolfi, Sara and Bender, Samantha and Bryan, Jordan G and Zhu, Cong and Wang, Li and Tariq, Ifrah and Kamath, Govinda M and Simoes, Ricardo De Matos and Dhimolea, Eugen and Yu, Channing and Hu, Yiguo and Dufva, Olli and Giannakis, Marios and Vasilis Syrgkanis and Fraenkel, Ernest and Golub, Todd and Romee, Rizwan and Mustjoki, Satu and Culhane, Aedin C and Wieten, Lotte and Mitsiades, Constantine S}
}
@article {1603680,
	title = {Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer},
	journal = {Nat Commun},
	volume = {12},
	number = {1},
	year = {2021},
	month = {2021 06 17},
	pages = {3697},
	abstract = {Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a\&nbsp;first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.},
	keywords = {Acrylamides, Aniline Compounds, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Survival, Cohort Studies, Computer Simulation, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Lung Neoplasms, Models, Statistical, Models, Theoretical, Mutation, Quinazolinones},
	issn = {2041-1723},
	doi = {10.1038/s41467-021-23912-4},
	author = {Poels, Kamrine E and Schoenfeld, Adam J and Makhnin, Alex and Tobi, Yosef and Wang, Yuli and Frisco-Cabanos, Heidie and Chakrabarti, Shaon and Shi, Manli and Napoli, Chelsi and McDonald, Thomas O and Tan, Weiwei and Hata, Aaron and Weinrich, Scott L and Yu, Helena A and Michor, Franziska}
}
@article {1603685,
	title = {Inhibition of CDK4/6 Promotes CD8 T-cell Memory Formation},
	journal = {Cancer Discov},
	volume = {11},
	number = {10},
	year = {2021},
	month = {2021 Oct},
	pages = {2564-2581},
	abstract = {CDK4/6 inhibitors are approved to treat breast cancer and are in trials for other malignancies. We examined CDK4/6 inhibition in mouse and human CD8+ T cells during early stages of activation. Mice receiving tumor-specific CD8+ T cells treated with CDK4/6 inhibitors displayed increased T-cell persistence and immunologic memory. CDK4/6 inhibition upregulated MXD4, a negative regulator of MYC, in both mouse and human CD8+ T cells. Silencing of Mxd4 or Myc in mouse CD8+ T cells demonstrated the importance of this axis for memory formation. We used single-cell transcriptional profiling and T-cell receptor clonotype tracking to evaluate recently activated human CD8+ T cells in patients with breast cancer before and during treatment with either palbociclib or abemaciclib. CDK4/6 inhibitor therapy in humans increases the frequency of CD8+ memory precursors and downregulates their expression of MYC target genes, suggesting that CDK4/6 inhibitors in patients with cancer may augment long-term protective immunity. SIGNIFICANCE: CDK4/6 inhibition skews newly activated CD8+ T cells toward a memory phenotype in mice and humans with breast cancer. CDK4/6 inhibitors may have broad utility outside breast cancer, particularly in the neoadjuvant setting to augment CD8+ T-cell priming to tumor antigens prior to dosing with checkpoint blockade.This article is highlighted in the In This Issue feature, p. 2355.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-20-1540},
	author = {Heckler, Max and Ali, Lestat R and Clancy-Thompson, Eleanor and Qiang, Li and Ventre, Katherine S and Lenehan, Patrick and Roehle, Kevin and Luoma, Adrienne and Boelaars, Kelly and Peters, Vera and McCreary, Julia and Boschert, Tamara and Wang, Eric S and Suo, Shengbao and Marangoni, Francesco and Mempel, Thorsten R and Long, Henry W and Wucherpfennig, Kai W and Dougan, Michael and Gray, Nathanael S and Yuan, Guo-Cheng and Goel, Shom and Tolaney, Sara M and Dougan, Stephanie K}
}
@article {1603678,
	title = {RASAL2 Confers Collateral MEK/EGFR Dependency in Chemoresistant Triple-Negative Breast Cancer},
	journal = {Clin Cancer Res},
	volume = {27},
	number = {17},
	year = {2021},
	month = {2021 09 01},
	pages = {4883-4897},
	abstract = {PURPOSE: While chemotherapy remains the standard treatment for triple-negative breast cancer (TNBC), identifying and managing chemoresistant tumors has proven elusive. We sought to discover hallmarks and therapeutically actionable features of refractory TNBC through molecular analysis of primary chemoresistant TNBC specimens.

EXPERIMENTAL DESIGN: We performed transcriptional profiling of tumors from a phase II clinical trial of platinum chemotherapy for advanced TNBC (TBCRC-009), revealing a gene expression signature that identified de novo chemorefractory tumors. We then employed pharmacogenomic data mining, proteomic and other molecular studies to define the therapeutic vulnerabilities of these tumors.

RESULTS: We reveal the RAS-GTPase-activating protein (RAS-GAP) RASAL2 as an upregulated factor that mediates chemotherapy resistance but also an exquisite collateral sensitivity to combination MAP kinase kinase (MEK1/2) and EGFR inhibitors in TNBC. Mechanistically, RASAL2 GAP activity is required to confer kinase inhibitor sensitivity, as RASAL2-high TNBCs sustain basal RAS activity through suppression of negative feedback regulators SPRY1/2, together with EGFR upregulation. Consequently, RASAL2 expression results in failed feedback compensation upon co-inhibition of MEK1/2 and EGFR that induces synergistic apoptosis in vitro and in vivo. In patients with TNBC, high RASAL2 levels predict clinical chemotherapy response and long-term outcomes, and are associated via direct transcriptional regulation with activated oncogenic Yes-Associated Protein (YAP). Accordingly, chemorefractory patient-derived TNBC models exhibit YAP activation, high RASAL2 expression, and tumor regression in response to MEK/EGFR inhibitor combinations despite well-tolerated intermittent dosing.

CONCLUSIONS: These findings identify RASAL2 as a mediator of TNBC chemoresistance that rewires MAPK feedback and cross-talk to confer profound collateral sensitivity to combination MEK1/2 and EGFR inhibitors.},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-21-0714},
	author = {Koh, Siang-Boon and Ross, Kenneth and Isakoff, Steven J and Melkonjan, Nsan and He, Lei and Matissek, Karina J and Schultz, Andrew and Mayer, Erica L and Traina, Tiffany A and Carey, Lisa A and Rugo, Hope S and Liu, Minetta C and Stearns, Vered and Langenbucher, Adam and Saladi, Srinivas Vinod and Ramaswamy, Sridhar and Lawrence, Michael S and Ellisen, Leif W}
}
@article {1603681,
	title = {REV7 directs DNA repair pathway choice},
	journal = {Trends Cell Biol},
	year = {2021},
	month = {2021 Jun 16},
	abstract = {REV7 is a small multifunctional protein that participates in multiple DNA repair pathways, most notably translesion DNA synthesis and double-strand break (DSB) repair. While the role of REV7 in translesion synthesis has been known for several decades, its function in DSB repair is a recent discovery. Investigations into the DSB repair function of REV7 have led to the discovery of a new DNA repair complex known as Shieldin. Recent studies have also highlighted the importance of REV7{\textquoteright}s HORMA domain, an ancient structural motif, in REV7 function and have identified the HORMA regulators, TRIP13 and p31, as novel DNA repair factors. In this review, we discuss these recent findings and their implications for repair pathway choice, at both DSBs and replication forks. We suggest that REV7, in particular the activation state of its HORMA domain, can act as a critical determinant of mutagenic versus error-free repair in multiple contexts.},
	issn = {1879-3088},
	doi = {10.1016/j.tcb.2021.05.009},
	author = {Clairmont, Connor S and D{\textquoteright}Andrea, Alan D}
}
@article {1603674,
	title = {SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis},
	journal = {Cell Rep},
	volume = {36},
	number = {2},
	year = {2021},
	month = {2021 07 13},
	pages = {109345},
	abstract = {Upon nutrient stimulation, pre-adipocytes undergo differentiation to transform into mature adipocytes capable of storing nutrients as fat. We profiled cellular metabolite consumption to identify early metabolic drivers of adipocyte differentiation. We find that adipocyte differentiation raises the uptake and consumption of numerous amino acids. In particular, branched-chain amino acid (BCAA) catabolism precedes and promotes peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of adipogenesis. In early adipogenesis, the mitochondrial sirtuin SIRT4 elevates BCAA catabolism through the activation of methylcrotonyl-coenzyme A (CoA) carboxylase (MCCC). MCCC supports leucine oxidation by catalyzing the carboxylation of 3-methylcrotonyl-CoA to 3-methylglutaconyl-CoA. Sirtuin 4 (SIRT4) expression is decreased in adipose tissue of numerous diabetic mouse models, and its expression is most correlated with BCAA enzymes, suggesting a potential role for SIRT4 in adipose pathology through the alteration of BCAA metabolism. In summary, this work provides a temporal analysis of adipocyte differentiation and uncovers early metabolic events that stimulate transcriptional reprogramming.},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2021.109345},
	author = {Zaganjor, Elma and Yoon, Haejin and Spinelli, Jessica B and Nunn, Elizabeth R and Laurent, Ga{\"e}lle and Keskinidis, Paulina and Sivaloganathan, Suganja and Joshi, Shakchhi and Notarangelo, Giulia and Mulei, Stacy and Chvasta, Mathew T and Tucker, Sarah A and Kalafut, Krystle and van de Ven, Robert A H and Clish, Clary B and Haigis, Marcia C}
}
@article {1589997,
	title = {Breast tumours maintain a reservoir of subclonal diversity during expansion},
	journal = {Nature},
	volume = {592},
	number = {7853},
	year = {2021},
	month = {2021 Apr},
	pages = {302-308},
	abstract = {Our knowledge of copy number evolution during the expansion of primary breast tumours is limited. Here, to investigate this process, we developed a single-cell, single-molecule DNA-sequencing method and performed copy number analysis of 16,178~single cells from 8 human triple-negative breast cancers and 4 cell lines. The results show that breast tumours and cell lines comprise a large milieu of subclones (7-22) that are organized into a few (3-5) major superclones. Evolutionary analysis suggests that after clonal TP53 mutations, multiple loss-of-heterozygosity events and genome doubling, there was a period of transient genomic instability followed by ongoing copy number evolution during the primary tumour expansion. By subcloning single daughter cells in culture, we show that tumour cells rediversify their genomes and do not retain isogenic properties. These data show that triple-negative breast cancers continue to evolve chromosome aberrations and maintain a reservoir of subclonal diversity during primary tumour growth.},
	issn = {1476-4687},
	doi = {10.1038/s41586-021-03357-x},
	author = {Minussi, Darlan C and Nicholson, Michael D and Ye, Hanghui and Davis, Alexander and Wang, Kaile and Baker, Toby and Tarabichi, Maxime and Sei, Emi and Du, Haowei and Rabbani, Mashiat and Peng, Cheng and Hu, Min and Bai, Shanshan and Lin, Yu-Wei and Schalck, Aislyn and Multani, Asha and Ma, Jin and McDonald, Thomas O and Casasent, Anna and Barrera, Angelica and Chen, Hui and Lim, Bora and Arun, Banu and Meric-Bernstam, Funda and Van Loo, Peter and Michor, Franziska and Navin, Nicholas E}
}
@article {1589996,
	title = {Chromothripsis as an on-target consequence of CRISPR-Cas9 genome editing},
	journal = {Nat Genet},
	volume = {53},
	number = {6},
	year = {2021},
	month = {2021 06},
	pages = {895-905},
	abstract = {Genome editing has therapeutic potential for treating genetic diseases and cancer. However, the currently most practicable approaches rely on the generation of DNA double-strand breaks (DSBs), which can give rise to a poorly characterized spectrum of chromosome structural abnormalities. Here, using model cells and single-cell whole-genome sequencing, as well as by editing at a clinically relevant locus in clinically relevant cells, we show that CRISPR-Cas9 editing generates structural defects of the nucleus, micronuclei and chromosome bridges, which initiate a mutational process called chromothripsis. Chromothripsis is extensive chromosome rearrangement restricted to one or a few chromosomes that can cause human congenital disease and cancer. These results demonstrate that chromothripsis is a previously unappreciated on-target consequence of CRISPR-Cas9-generated DSBs. As genome editing is implemented in the clinic, the potential for extensive chromosomal rearrangements should be considered and monitored.},
	keywords = {Anemia, Sickle Cell, Antigens, CD34, Cell Division, Chromosomes, Human, Chromothripsis, CRISPR-Associated Protein 9, CRISPR-Cas Systems, DNA Cleavage, Gene Editing, Genome, Human, Humans, Micronucleus, Germline, Tumor Suppressor Protein p53},
	issn = {1546-1718},
	doi = {10.1038/s41588-021-00838-7},
	author = {Leibowitz, Mitchell L and Papathanasiou, Stamatis and Doerfler, Phillip A and Blaine, Logan J and Sun, Lili and Yao, Yu and Zhang, Cheng-Zhong and Weiss, Mitchell J and Pellman, David}
}
@article {1589995,
	title = {The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2+ breast cancer},
	journal = {JCI Insight},
	volume = {6},
	number = {11},
	year = {2021},
	month = {2021 06 08},
	abstract = {Despite the availability of multiple human epidermal growth factor receptor 2-targeted (HER2-targeted) treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations in the PIK3CA gene (encoding PI3K catalytic subunit α) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes and tumor epithelial-stromal cell interactions is less well understood. Here, we assessed the effect of intratumor cellular genetic heterogeneity for ERBB2 (encoding HER2) copy number and PIK3CA mutation on different types of neoadjuvant HER2-targeting therapies and clinical outcome in HER2+ breast cancer. We found that the frequency of cells lacking HER2 was a better predictor of response to HER2-targeted treatment than intratumor heterogeneity. We also compared the efficacy of different therapies in the same tumor using patient-derived xenograft models of heterogeneous HER2+ breast cancer and single-cell approaches. Stromal determinants were better predictors of response than tumor epithelial cells, and we identified alveolar epithelial and fibroblastic reticular cells as well as lymphatic vessel endothelial hyaluronan receptor 1-positive (Lyve1+) macrophages as putative drivers of therapeutic resistance. Our results demonstrate that both preexisting and acquired resistance to HER2-targeting agents involve multiple mechanisms including the tumor microenvironment. Furthermore, our data suggest that intratumor heterogeneity for HER2 should be incorporated into treatment design.},
	issn = {2379-3708},
	doi = {10.1172/jci.insight.147617},
	author = {Janiszewska, Michalina and Stein, Shayna and Metzger Filho, Otto and Eng, Jennifer and Kingston, Natalie L and Harper, Nicholas W and Rye, Inga H and Ale{\v c}kovi{\'c}, Ma{\v s}a and Trinh, Anne and Murphy, Katherine C and Marangoni, Elisabetta and Cristea, Simona and Oakes, Benjamin and Winer, Eric P and Krop, Ian E and Russnes, Hege G and Spellman, Paul T and Bucher, Elmar and Hu, Zhi and Chin, Koei and Gray, Joe W and Michor, Franziska and Polyak, Kornelia}
}
@article {1589998,
	title = {KRAS G12C inhibition and innate immune targeting},
	journal = {Expert Opin Ther Targets},
	year = {2021},
	month = {2021 Mar 28},
	pages = {1-8},
	abstract = {INTRODUCTION:  mutations drive tumorigenesis by altering cell signaling and the tumor immune microenvironment. Recent studies have shown promise for KRAS-G12C covalent inhibitors, which are advancing rapidly through clinical trials. The sequencing and combination of these agents with other therapies including immune checkpoint blockade (ICB) will benefit from strategies that also address the immune microenvironment to improve durability of response.

AREAS COVERED: This paper reviews KRAS signaling and discusses downstream effects on cytokine production and the tumor immune microenvironment. RAS targeted therapy is introduced and perspectives on therapeutic targeting of KRAS-G12C and its immunosuppressive tumor microenvironment are offered.

EXPERT OPINION: The availability of KRAS-G12C covalent inhibitors raises hopes for targeting this pervasive oncogene and designing better therapeutic combinations to promote anti-tumor immunity. A comprehensive mechanistic understanding of KRAS immunosuppression is required in order to prioritize agents for clinical trials.},
	issn = {1744-7631},
	doi = {10.1080/14728222.2021.1902991},
	author = {Tani, Tetsuo and Kitajima, Shunsuke and Conway, Ella B and Knelson, Erik H and Barbie, David A}
}
@article {1590000,
	title = {Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion},
	journal = {Nat Genet},
	volume = {53},
	number = {3},
	year = {2021},
	month = {2021 03},
	pages = {332-341},
	abstract = {Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)-JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion.},
	keywords = {CD58 Antigens, Coculture Techniques, Computational Biology, CRISPR-Cas Systems, Drug Resistance, Neoplasm, Epitopes, Gene Knockout Techniques, Humans, Immune Checkpoint Inhibitors, Interferon-gamma, Lymphocytes, Tumor-Infiltrating, Melanoma, Sequence Analysis, RNA, Single-Cell Analysis, Tumor Escape},
	issn = {1546-1718},
	doi = {10.1038/s41588-021-00779-1},
	author = {Frangieh, Chris J and Melms, Johannes C and Thakore, Pratiksha I and Geiger-Schuller, Kathryn R and Ho, Patricia and Luoma, Adrienne M and Cleary, Brian and Jerby-Arnon, Livnat and Malu, Shruti and Cuoco, Michael S and Zhao, Maryann and Ager, Casey R and Rogava, Meri and Hovey, Lila and Rotem, Asaf and Bernatchez, Chantale and Wucherpfennig, Kai W and Johnson, Bruce E and Rozenblatt-Rosen, Orit and Schadendorf, Dirk and Regev, Aviv and Izar, Benjamin}
}
@article {1589999,
	title = {Understanding and treating the inflammatory adverse events of cancer immunotherapy},
	journal = {Cell},
	volume = {184},
	number = {6},
	year = {2021},
	month = {2021 Mar 18},
	pages = {1575-1588},
	abstract = {During the past decade, immunotherapies have made a major impact on the treatment of diverse types of cancer. Inflammatory toxicities are not only a major concern for Food and Drug Administration (FDA)-approved checkpoint blockade and chimeric antigen receptor (CAR) T~cell therapies, but also limit the development and use of combination therapies. Fundamentally, these adverse events highlight the intricate balance of pro- and anti-inflammatory pathways that regulate protective immune responses. Here, we discuss the cellular and molecular mechanisms of inflammatory adverse events, current approaches to treatment, as well as opportunities for the design of immunotherapies that limit such inflammatory toxicities while preserving anti-tumor efficacy.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2021.02.011},
	author = {Dougan, Michael and Luoma, Adrienne M and Dougan, Stephanie K and Wucherpfennig, Kai W}
}
@article {1586657,
	title = {The aging lung: Physiology, disease, and immunity},
	journal = {Cell},
	year = {2021},
	month = {2021 Mar 26},
	abstract = {The population is aging at a rate never seen before in human history. As the number of elderly adults grows, it is imperative we expand our understanding of the underpinnings of aging biology. Human lungs are composed of a unique panoply of cell types that face ongoing chemical, mechanical, biological, immunological, and xenobiotic stress over a lifetime. Yet, we do not fully appreciate the mechanistic drivers of lung aging and why age increases the risk of parenchymal lung disease, fatal respiratory infection, and primary lung cancer. Here, we review the molecular and cellular aspects of lung aging, local stress response pathways, and how the aging process predisposes to the pathogenesis of pulmonary disease. We place these insights into context of the COVID-19 pandemic and discuss how innate and adaptive immunity within the lung is altered with age.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2021.03.005},
	author = {Schneider, Jaime L and Rowe, Jared H and Garcia-de-Alba, Carolina and Kim, Carla F and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1586659,
	title = {Intrinsic immunogenicity of small cell lung carcinoma revealed by its cellular plasticity},
	journal = {Cancer Discov},
	year = {2021},
	month = {2021 Mar 11},
	abstract = {Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with de-repression of STING. Transient EZH2 inhibition expands these non-neuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine non-neuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC{\textquoteright}s intrinsic immunogenicity.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-20-0913},
	author = {Mahadevan, Navin R and Knelson, Erik H and Wolff, Jacquelyn O and Vajdi, Amir and Saigi, Maria and Campisi, Marco and Hong, Deli and Thai, Tran C and Piel, Brandon and Han, Saemi and Reinhold, Bruce B and Duke-Cohan, Jonathan S and Poitras, Michael J and Taus, Luke J and Lizotte, Patrick H and Portell, Andrew and Quadros, Victor and Santucci, Alison D and Murayama, Takahiko and Canadas, Israel and Kitajima, Shunsuke and Akitsu, Aoi and Fridrikh, Maya and Watanabe, Hideo and Reardon, Brendan and Gokhale, Prafulla C and Paweletz, Cloud P and Awad, Mark M and Van Allen, Eliezer M and Lako, Ana and Wang, Xi-Tao and Chen, Benjamin and Hong, Fangxin and Sholl, Lynette M and Tolstorukov, Michael Y and Pfaff, Kathleen and Janne, Pasi A and Gjini, Evisa and Edwards, Robin and Rodig, Scott and Reinherz, Ellis L and Oser, Matthew G and Barbie, David A}
}
@article {1586658,
	title = {Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer},
	journal = {Nat Cancer},
	volume = {2},
	number = {1},
	year = {2021},
	month = {2021 Jan},
	pages = {66-82},
	abstract = {Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Combined PARP inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.},
	issn = {2662-1347},
	doi = {10.1038/s43018-020-00148-7},
	author = {Mehta, Anita K and Cheney, Emily M and Hartl, Christina A and Pantelidou, Constantia and Oliwa, Madisson and Castrillon, Jessica A and Lin, Jia-Ren and Hurst, Katie E and de Oliveira Taveira, Mateus and Johnson, Nathan T and Oldham, William M and Kalocsay, Marian and Berberich, Matthew J and Boswell, Sarah A and Kothari, Aditi and Johnson, Shawn and Dillon, Deborah A and Lipschitz, Mikel and Rodig, Scott and Santagata, Sandro and Garber, Judy E and Tung, Nadine and Y{\'e}lamos, Jos{\'e} and Thaxton, Jessica E and Mittendorf, Elizabeth A and Sorger, Peter K and Shapiro, Geoffrey I and Guerriero, Jennifer L}
}
@article {1582380,
	title = {CellBox: Interpretable Machine Learning for Perturbation Biology with Application to the Design of Cancer Combination Therapy},
	journal = {Cell Syst},
	volume = {12},
	number = {2},
	year = {2021},
	month = {2021 Feb 17},
	pages = {128-140.e4},
	abstract = {Systematic perturbation of cells followed by comprehensive measurements of molecular and phenotypic responses provides informative data resources for constructing computational models of cell biology. Models that generalize well beyond training data can be used to identify combinatorial perturbations of potential therapeutic interest. Major challenges for machine learning on large biological datasets are to find global optima in a complex multidimensional space and mechanistically interpret the solutions. To address these challenges, we introduce a hybrid approach that combines explicit mathematical models of cell dynamics with a machine-learning framework, implemented in TensorFlow. We tested the modeling framework on a perturbation-response dataset of a melanoma cell line after drug treatments. The models can be efficiently trained to describe cellular behavior accurately. Even though completely data driven and independent of prior knowledge, the resulting de novo network models recapitulate some known interactions. The approach is readily applicable to various kinetic models of cell biology. A record of this paper{\textquoteright}s Transparent Peer Review process is included in the Supplemental Information.},
	issn = {2405-4720},
	doi = {10.1016/j.cels.2020.11.013},
	author = {Yuan, Bo and Shen, Ciyue and Luna, Augustin and Korkut, Anil and Marks, Debora S and Ingraham, John and Sander, Chris}
}
@article {1572222,
	title = {Self-organization in cancer: implications for histopathology, cancer cell biology, and metastasis},
	journal = {Cancer Cell},
	year = {2021},
	abstract = {Pathologists use histological features to classify tumors and assign site of origin for metastasis. How and why tumors organize the way they do and recreate their histological organization during metastasis is unknown. Here, I discuss the concept of {\textquotedblleft}histostasis{\textquotedblright} conferring tumors a histological memory and hypothesize its implications for metastasis.},
	url = {https://www-sciencedirect-com.ezp-prod1.hul.harvard.edu/science/article/pii/S1535610821000544},
	author = {Muthuswamy, Senthil K}
}
@article {1572206,
	title = {Clinical Efficacy and Molecular Response Correlates of the WEE1 Inhibitor Adavosertib Combined with Cisplatin in Patients with Metastatic Triple-Negative Breast Cancer},
	journal = {Clin Cancer Res},
	volume = {27},
	number = {4},
	year = {2021},
	month = {2021 02 15},
	pages = {983-991},
	abstract = {PURPOSE: We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC).

PATIENTS AND METHODS: Patients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m2 i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90\% power to detect the difference between null (20\%) and alternative (40\%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR \&gt;30\% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease >=6 months or complete or partial response.

RESULTS: A total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6\%) had BRCA2 mutations, and 14 (41\%) had one prior chemotherapy. ORR was 26\% [95\% confidence interval (CI), 13-44], and median progression-free survival was 4.9 months (95\% CI, 2.3-5.7). Treatment-related grade 3-5 adverse events occurred in 53\% of patients, most commonly diarrhea in 21\%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration.

CONCLUSIONS: Among patients with mTNBC treated with 0-1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of \&gt;30\%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.},
	keywords = {Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Cell Cycle Proteins, Chemotherapy, Adjuvant, cisplatin, Female, Humans, Middle Aged, progression-free survival, Protein-Tyrosine Kinases, Pyrazoles, Pyrimidinones, Triple Negative Breast Neoplasms, Young Adult},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-20-3089},
	author = {Keenan, Tanya E and Li, Tianyu and Vallius, Tuulia and Guerriero, Jennifer L and Tayob, Nabihah and Kochupurakkal, Bose and Davis, Janae and Pastorello, Ricardo and Tahara, Rie K and Anderson, Leilani and Conway, Jake and He, Meng X and Shannon, Erin and Godin, Robert E and Sorger, Peter K and D{\textquoteright}Andrea, Alan and Overmoyer, Beth and Winer, Eric P and Mittendorf, Elizabeth A and Van Allen, Eliezer M and Shapiro, Geoffrey I and Tolaney, Sara M}
}
@article {1572211,
	title = {Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade},
	journal = {J Clin Invest},
	volume = {131},
	number = {2},
	year = {2021},
	month = {2021 Jan 19},
	abstract = {Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.},
	issn = {1558-8238},
	doi = {10.1172/JCI135038},
	author = {Sehgal, Kartik and Portell, Andrew and Ivanova, Elena V and Lizotte, Patrick H and Mahadevan, Navin R and Greene, Jonathan R and Vajdi, Amir and Gurjao, Carino and Teceno, Tyler and Taus, Luke J and Thai, Tran C and Kitajima, Shunsuke and Liu, Derek and Tani, Tetsuo and Noureddine, Moataz and Lau, Christie J and Kirschmeier, Paul T and Liu, David and Giannakis, Marios and Jenkins, Russell W and Gokhale, Prafulla C and Goldoni, Silvia and Pinzon-Ortiz, Maria and Hastings, William D and Hammerman, Peter S and Miret, Juan J and Paweletz, Cloud P and Barbie, David A}
}
@article {1572198,
	title = {HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor},
	journal = {Clin Cancer Res},
	volume = {27},
	number = {6},
	year = {2021},
	month = {2021 03 15},
	pages = {1706-1719},
	abstract = {PURPOSE: Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine GIST more aggressive, a molecular understanding of disease behavior would inform therapy decisions in GIST. Although a core transcription factor (TF) network is conserved across GIST, accessory TFs HAND1 and BARX1 are expressed in a disease state-specific pattern. Here, we characterize two divergent transcriptional programs maintained by HAND1 and BARX1, and evaluate their association with clinical outcomes.

EXPERIMENTAL DESIGN: We evaluated RNA sequencing and TF chromatin immunoprecipitation with sequencing in GIST samples and cultured cells for transcriptional programs associated with HAND1 and BARX1. Multiplexed tissue-based cyclic immunofluorescence and IHC evaluated tissue- and cell-level expression of TFs and their association with clinical factors.

RESULTS: We show that HAND1 is expressed in aggressive GIST, modulating KIT and core TF expression and supporting proliferative cellular programs. In contrast, BARX1 is expressed in indolent and micro-GISTs. HAND1 and BARX1 expression were superior predictors of relapse-free survival, as compared with standard risk stratification, and they predict progression-free survival on imatinib. Reflecting the developmental origins of accessory TF programs, HAND1 was expressed solely in small intestine ICCs, whereas BARX1 expression was restricted to gastric ICCs.

CONCLUSIONS: Our results define anatomic and transcriptional determinants of GIST and molecular origins of clinical phenotypes. Assessment of HAND1 and BARX1 expression in GIST may provide prognostic information and improve clinical decisions on the administration of adjuvant therapy.},
	issn = {1557-3265},
	doi = {10.1158/1078-0432.CCR-20-3538},
	author = {Hemming, Matthew L and Coy, Shannon and Lin, Jia-Ren and Andersen, Jessica L and Przybyl, Joanna and Mazzola, Emanuele and Abdelhamid Ahmed, Amr H and van de Rijn, Matt and Sorger, Peter K and Armstrong, Scott A and Demetri, George D and Santagata, Sandro}
}
@article {1572201,
	title = {Integrin αvβ6-TGFβ-SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer},
	journal = {Cancer Cell},
	volume = {39},
	number = {1},
	year = {2021},
	month = {2021 01 11},
	pages = {54-67.e9},
	abstract = {Cancer immunotherapy shows limited efficacy against many solid tumors that originate from epithelial tissues, including triple-negative breast cancer (TNBC). We identify the SOX4 transcription factor as an important resistance mechanism to T~cell-mediated cytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation of SOX4 in tumor cells increases the expression of genes in a number of innate and adaptive immune pathways important for protective tumor immunity. Expression of SOX4 is regulated by the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβ from a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibits SOX4 expression and sensitizes TNBC cells to cytotoxic T~cells. This integrin mAb induces a substantial survival benefit in highly metastatic murine TNBC models poorly responsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ-SOX4 pathway therefore provides therapeutic opportunities for TNBC and other highly aggressive human cancers of epithelial origin.},
	keywords = {Animals, Antibodies, Monoclonal, Antigens, Neoplasm, Antineoplastic Agents, Immunological, Cell Line, Tumor, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Integrins, Mice, Neoplasm Transplantation, Sequence Analysis, RNA, Signal Transduction, SOXC Transcription Factors, T-Lymphocytes, Cytotoxic, Transforming Growth Factor beta, Triple Negative Breast Neoplasms, Tumor Escape, Xenograft Model Antitumor Assays},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2020.12.001},
	author = {Bagati, Archis and Kumar, Sushil and Jiang, Peng and Pyrdol, Jason and Zou, Angela E and Godicelj, Anze and Mathewson, Nathan D and Cartwright, Adam N R and Cejas, Paloma and Brown, Myles and Giobbie-Hurder, Anita and Dillon, Deborah and Agudo, Judith and Mittendorf, Elizabeth A and Liu, X Shirley and Wucherpfennig, Kai W}
}
@article {1572200,
	title = {Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism},
	journal = {Nat Metab},
	volume = {3},
	number = {1},
	year = {2021},
	month = {2021 Jan},
	pages = {21-32},
	abstract = {Metabolic transformation is a hallmark of cancer and a critical target for cancer therapy. Cancer metabolism and behaviour are regulated by cell-intrinsic factors as well as metabolite availability in the tumour microenvironment (TME). This metabolic niche within the TME is shaped by four tiers of regulation: (1) intrinsic tumour cell metabolism, (2) interactions between cancer cells and non-cancerous cells, (3) tumour location and heterogeneity and (4) whole-body metabolic homeostasis. Here, we define these modes of metabolic regulation and review how distinct cell types contribute to the metabolite composition of the TME. Finally, we connect these insights to understand how each of these tiers offers unique therapeutic potential to modulate the metabolic profile and function of all cells inhabiting the TME.},
	issn = {2522-5812},
	doi = {10.1038/s42255-020-00317-z},
	author = {Elia, Ilaria and Haigis, Marcia C}
}
@article {1572204,
	title = {Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8 T Cells},
	journal = {Cancer Immunol Res},
	volume = {9},
	number = {2},
	year = {2021},
	month = {2021 02},
	pages = {184-199},
	abstract = {Metabolic constraints in the tumor microenvironment constitute a barrier to effective antitumor immunity and similarities in the metabolic properties of T cells and cancer cells impede the specific therapeutic targeting of metabolism in either population. To identify distinct metabolic vulnerabilities of CD8+ T cells and cancer cells, we developed a high-throughput in vitro pharmacologic screening platform and used it to measure the cell type-specific sensitivities of activated CD8+ T cells and B16 melanoma cells to a wide array of metabolic perturbations during antigen-specific killing of cancer cells by CD8+ T cells. We illustrated the applicability of this screening platform by showing that CD8+ T cells were more sensitive to ferroptosis induction by inhibitors of glutathione peroxidase 4 (GPX4) than B16 and MC38 cancer cells. Overexpression of ferroptosis suppressor protein 1 (FSP1) or cytosolic GPX4 yielded ferroptosis-resistant CD8+ T cells without compromising their function, while genetic deletion of the ferroptosis sensitivity-promoting enzyme acyl-CoA synthetase long-chain family member 4 (ACSL4) protected CD8+ T cells from ferroptosis but impaired antitumor CD8+ T-cell responses. Our screen also revealed high T cell-specific vulnerabilities for compounds targeting NAD+ metabolism or autophagy and endoplasmic reticulum (ER) stress pathways. We focused the current screening effort on metabolic agents. However, this in vitro screening platform may also be valuable for rapid testing of other types of compounds to identify regulators of antitumor CD8+ T-cell function and potential therapeutic targets.},
	keywords = {Animals, Antineoplastic Agents, Autophagy, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Endoplasmic Reticulum, Female, Ferroptosis, Humans, Mice, Mice, Inbred C57BL, Neoplasms, Tumor Cells, Cultured},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-20-0384},
	author = {Drijvers, Jefte M and Gillis, Jacob E and Muijlwijk, Tara and Nguyen, Thao H and Gaudiano, Emily F and Harris, Isaac S and LaFleur, Martin W and Ringel, Alison E and Yao, Cong-Hui and Kurmi, Kiran and Juneja, Vikram R and Trombley, Justin D and Haigis, Marcia C and Sharpe, Arlene H}
}
@article {1641524,
	title = {3D Culture Models with CRISPR Screens Reveal Hyperactive NRF2 as a Prerequisite for Spheroid Formation via Regulation of Proliferation and Ferroptosis},
	journal = {Mol Cell},
	volume = {80},
	number = {5},
	year = {2020},
	month = {2020 12 03},
	pages = {828-844.e6},
	abstract = {Cancer-associated mutations that stabilize NRF2, an oxidant defense transcription factor, are predicted to promote tumor development. Here, utilizing 3D cancer spheroid models coupled with CRISPR-Cas9 screens, we investigate the molecular pathogenesis mediated by NRF2 hyperactivation. NRF2 hyperactivation was necessary for proliferation and survival in lung tumor spheroids. Antioxidant treatment rescued survival but not proliferation, suggesting the presence of distinct mechanisms. CRISPR screens revealed that spheroids are differentially dependent on the mammalian target of rapamycin (mTOR) for proliferation and the lipid peroxidase GPX4 for protection from ferroptosis of inner, matrix-deprived cells. Ferroptosis inhibitors blocked death from NRF2 downregulation, demonstrating a critical role of NRF2 in protecting matrix-deprived cells from ferroptosis. Interestingly, proteomics analyses show global enrichment of selenoproteins, including GPX4, by NRF2 downregulation, and targeting NRF2 and GPX4 killed spheroids overall. These results illustrate the value of spheroid culture in revealing environmental or spatial differential dependencies on NRF2 and reveal exploitable vulnerabilities of NRF2-hyperactivated tumors.},
	keywords = {A549 Cells, Cell Culture Techniques, Cell Proliferation, CRISPR-Cas Systems, Ferroptosis, Humans, Neoplasm Proteins, Neoplasms, NF-E2-Related Factor 2, Phospholipid Hydroperoxide Glutathione Peroxidase, Spheroids, Cellular, TOR Serine-Threonine Kinases},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2020.10.010},
	author = {Nobuaki Takahashi and Cho, Patricia and Selfors, Laura M and Kuiken, Hendrik J and Kaul, Roma and Fujiwara, Takuro and Harris, Isaac S and Zhang, Tian and Gygi, Steven P and Brugge, Joan S}
}
@article {1641526,
	title = {Fibroblast-tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways},
	journal = {Proc Natl Acad Sci U S A},
	volume = {117},
	number = {28},
	year = {2020},
	month = {2020 07 14},
	pages = {16500-16508},
	abstract = {Despite the implementation of multiple HER2-targeted therapies, patients with advanced HER2+ breast cancer ultimately develop drug resistance. Stromal fibroblasts represent an abundant cell type in the tumor microenvironment and have been linked to poor outcomes and drug resistance. Here, we show that fibroblasts counteract the cytotoxic effects of HER2 kinase-targeted therapy in a subset of HER2+ breast cancer cell lines and allow cancer cells to proliferate in the presence of the HER2 kinase inhibitor lapatinib. Fibroblasts from primary breast tumors, normal breast tissue, and lung tissue have similar protective effects on tumor cells via paracrine factors. This fibroblast-mediated reduction in drug sensitivity involves increased expression of antiapoptotic proteins and sustained activation of the PI3K/AKT/MTOR pathway, despite inhibition of the HER2 and the RAS-ERK pathways in tumor cells. HER2 therapy sensitivity is restored in the fibroblast cocultures by combination treatment with inhibitors of MTOR or the antiapoptotic proteins BCL-XL and MCL-1. Expression of activated AKT in tumor cells recapitulates the effects of fibroblasts resulting in sustained MTOR signaling and poor lapatinib response. Lapatinib sensitivity was not altered by fibroblasts in tumor cells that exhibited sustained MTOR signaling due to a strong gain-of-function PI3KCA mutation. These findings indicate that in addition to tumor cell-intrinsic mechanisms that cause constitutive PI3K/AKT/MTOR pathway activation, secreted factors from fibroblasts can maintain this pathway in the context of HER2 inhibition. Our integrated proteomic-phenotypic approach presents a strategy for the discovery of protective mechanisms in fibroblast-rich tumors and the design of rational combination therapies to restore drug sensitivity.},
	keywords = {Antineoplastic Agents, Apoptosis, Breast Neoplasms, Cell Line, Tumor, Female, Fibroblasts, Humans, Lapatinib, Phosphatidylinositol 3-Kinases, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Signal Transduction, TOR Serine-Threonine Kinases},
	issn = {1091-6490},
	doi = {10.1073/pnas.2000648117},
	author = {Zervantonakis, Ioannis K and Poskus, Matthew D and Scott, Alexis L and Selfors, Laura M and Lin, Jia-Ren and Dillon, Deborah A and Pathania, Shailja and Sorger, Peter K and Mills, Gordon B and Brugge, Joan S}
}
@article {1641527,
	title = {Large-Scale Characterization of Drug Responses of Clinically Relevant Proteins in Cancer Cell Lines},
	journal = {Cancer Cell},
	volume = {38},
	number = {6},
	year = {2020},
	month = {2020 12 14},
	pages = {829-843.e4},
	abstract = {Perturbation biology is a powerful approach to modeling quantitative cellular behaviors and understanding detailed disease mechanisms. However, large-scale protein response resources of cancer cell lines to perturbations are not available, resulting in a critical knowledge gap. Here we generated and compiled perturbed expression profiles of \~{}210 clinically relevant proteins in \&gt;12,000 cancer cell line samples in response to \~{}170 drug compounds using reverse-phase protein arrays. We show that integrating perturbed protein response signals provides mechanistic insights into drug resistance, increases the predictive power for drug sensitivity, and helps identify effective drug combinations. We build a systematic map of "protein-drug" connectivity and develop a user-friendly data portal for community use. Our study provides a rich resource to investigate the behaviors of cancer cells and the dependencies of treatment responses, thereby enabling a broad range of biomedical applications.},
	keywords = {Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cell Survival, Computational Biology, Drug Resistance, Neoplasm, Humans, Molecular Targeted Therapy, Neoplasms, Protein Array Analysis, Protein Interaction Maps, Proteomics, User-Computer Interface},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2020.10.008},
	author = {Zhao, Wei and Li, Jun and Chen, Mei-Ju M and Luo, Yikai and Ju, Zhenlin and Nesser, Nicole K and Johnson-Camacho, Katie and Boniface, Christopher T and Lawrence, Yancey and Pande, Nupur T and Davies, Michael A and Herlyn, Meenhard and Muranen, Taru and Zervantonakis, Ioannis K and von Euw, Erika and Schultz, Andre and Kumar, Shwetha V and Korkut, Anil and Spellman, Paul T and Akbani, Rehan and Slamon, Dennis J and Gray, Joe W and Brugge, Joan S and Lu, Yiling and Mills, Gordon B and Liang, Han}
}
@article {1641523,
	title = {Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages},
	journal = {Nat Commun},
	volume = {11},
	number = {1},
	year = {2020},
	month = {2020 04 06},
	pages = {1711},
	abstract = {Recently, organoid technology has been used to generate a large repository of breast cancer organoids. Here we present an extensive evaluation of the ability of organoid culture technology to preserve complex stem/progenitor and differentiated cell types via long-term propagation of normal human mammary tissues. Basal/stem and luminal progenitor cells can differentiate in culture to generate mature basal and luminal cell types, including ER+ cells that have been challenging to maintain in culture. Cells associated with increased cancer risk can also be propagated. Single-cell analyses of matched organoid cultures and native tissues by mass cytometry for 38 markers provide a higher resolution representation of the multiple mammary epithelial cell types in the organoids, and demonstrate that protein expression patterns of the tissue of origin can be preserved in culture. These studies indicate that organoid cultures provide a valuable platform for studies of mammary differentiation, transformation, and breast cancer risk.},
	keywords = {Adult, BRCA1 Protein, Breast Neoplasms, Cell Culture Techniques, Cell Differentiation, Cell Lineage, Epidermal Growth Factor, ErbB Receptors, Female, Humans, Mammary Glands, Human, Middle Aged, Organoids, p38 Mitogen-Activated Protein Kinases, Single-Cell Analysis, Stem Cells, Transforming Growth Factor beta, Young Adult},
	issn = {2041-1723},
	doi = {10.1038/s41467-020-15548-7},
	author = {Rosenbluth, Jennifer M and Schackmann, Ron C J and Gray, G Kenneth and Selfors, Laura M and Li, Carman Man-Chung and Boedicker, Mackenzie and Kuiken, Hendrik J and Richardson, Andrea and Brock, Jane and Judy Garber and Dillon, Deborah and Sachs, Norman and Clevers, Hans and Brugge, Joan S}
}
@article {1641525,
	title = {Transient commensal clonal interactions can drive tumor metastasis},
	journal = {Nat Commun},
	volume = {11},
	number = {1},
	year = {2020},
	month = {2020 11 16},
	pages = {5799},
	abstract = {The extent and importance of functional heterogeneity and crosstalk between tumor cells is poorly understood. Here, we describe the generation of clonal populations from a patient-derived ovarian clear cell carcinoma model which forms malignant ascites and solid peritoneal tumors upon intraperitoneal transplantation in mice. The clonal populations are engineered with secreted Gaussia luciferase to monitor tumor growth dynamics and tagged with a unique DNA barcode to track their fate in multiclonal mixtures during tumor progression. Only one clone, CL31, grows robustly, generating exclusively malignant ascites. However, multiclonal mixtures form large solid peritoneal metastases, populated almost entirely by CL31, suggesting that transient cooperative interclonal interactions are sufficient to promote metastasis of CL31. CL31 uniquely harbors ERBB2 amplification, and its acquired metastatic activity in clonal mixtures is dependent on transient exposure to amphiregulin, which is exclusively secreted by non-tumorigenic clones. Amphiregulin enhances CL31 mesothelial clearance, a prerequisite for metastasis. These findings demonstrate that transient, ostensibly innocuous tumor subpopulations can promote metastases via "hit-and-run" commensal interactions.},
	keywords = {Amphiregulin, Animals, Ascites, Carcinogenesis, Carcinoma, Renal Cell, Cell Communication, Cell Line, Tumor, Cell Proliferation, Cell Separation, Clone Cells, Cohort Studies, DNA Copy Number Variations, Epithelium, Female, Gene Amplification, Humans, Kidney Neoplasms, Ligands, Mice, SCID, Models, Biological, Neoplasm Metastasis, Peritoneal Neoplasms, Phenotype, Receptor, ErbB-2, Time Factors},
	issn = {2041-1723},
	doi = {10.1038/s41467-020-19584-1},
	author = {Amara, Suha Naffar-Abu and Kuiken, Hendrik J and Selfors, Laura M and Butler, Timothy and Leung, Marco L and Leung, Cheuk T and Kuhn, Elaine P and Kolarova, Teodora and Hage, Carina and Ganesh, Kripa and Panayiotou, Richard and Foster, Rosemary and Rueda, Bo R and Aktipis, Athena and Spellman, Paul and Ince, Tan A and Xiu, Joanne and Oberley, Matthew and Gatalica, Zoran and Navin, Nicholas and Mills, Gordon B and Bronson, Rodrick T and Brugge, Joan S}
}
@article {1628709,
	title = {CHK1 Inhibitor Blocks Phosphorylation of FAM122A and Promotes Replication Stress},
	journal = {Mol Cell},
	volume = {80},
	number = {3},
	year = {2020},
	month = {2020 11 05},
	pages = {410-422.e6},
	abstract = {While effective anti-cancer drugs targeting the CHK1 kinase are advancing in the clinic, drug resistance is rapidly emerging. Here, we demonstrate that CRISPR-mediated knockout of the little-known gene FAM122A/PABIR1 confers cellular resistance to CHK1 inhibitors (CHK1is) and cross-resistance to ATR inhibitors. Knockout of FAM122A results in activation of PP2A-B55α, a phosphatase that dephosphorylates the WEE1 protein and rescues WEE1 from ubiquitin-mediated degradation. The resulting increase in WEE1 protein expression reduces replication stress, activates the G2/M checkpoint, and confers cellular resistance to CHK1is. Interestingly, in tumor cells with oncogene-driven replication stress, CHK1 can directly phosphorylate FAM122A, leading to activation of the PP2A-B55α phosphatase and increased WEE1 expression. A combination of a CHK1i plus a WEE1 inhibitor can overcome CHK1i resistance of these tumor cells, thereby enhancing anti-cancer activity. The FAM122A expression level in a tumor cell can serve as a useful biomarker for predicting CHK1i sensitivity or resistance.},
	keywords = {Animals, Apoptosis, Cell Cycle Checkpoints, Cell Cycle Proteins, Cell Line, Cell Line, Tumor, Cell Proliferation, Checkpoint Kinase 1, DNA Damage, G2 Phase Cell Cycle Checkpoints, Humans, Intracellular Signaling Peptides and Proteins, Nuclear Proteins, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, Protein Processing, Post-Translational, Protein-Tyrosine Kinases, Pyrazines, Pyrazoles, Signal Transduction},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2020.10.008},
	author = {Li, Feng and Kozono, David and Deraska, Peter and Branigan, Timothy and Dunn, Connor and Zheng, Xiao-Feng and Parmar, Kalindi and Nguyen, Huy and DeCaprio, James and Shapiro, Geoffrey I and Chowdhury, Dipanjan and D{\textquoteright}Andrea, Alan D}
}
@article {1628711,
	title = {Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance},
	journal = {Cell Metab},
	volume = {32},
	number = {3},
	year = {2020},
	month = {2020 09 01},
	pages = {391-403.e6},
	abstract = {Cancer relapse begins when malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the byproducts of the massive cell death in the surrounding region. In acute myeloid leukemia, complete remissions are common, but few are cured. We tracked leukemia cells in~vivo, defined the moment of maximal response following chemotherapy, captured persisting cells, and conducted unbiased metabolomics, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine and glutathione generation, but not the mitochondrial tricarboxylic acid cycle. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual leukemia-initiating cells and improved survival in leukemia mouse models and patient-derived xenografts. We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploit a transient vulnerability and induce metabolic collapse in cancer cells to overcome chemoresistance.},
	keywords = {Animals, Antineoplastic Agents, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute, Mice, Mice, Congenic, Mice, Inbred C57BL, Mice, Inbred NOD},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2020.07.009},
	author = {van Gastel, Nick and Spinelli, Jessica B and Sharda, Azeem and Schajnovitz, Amir and Baryawno, Ninib and Rhee, Catherine and Oki, Toshihiko and Grace, Eliane and Soled, Heather J and Milosevic, Jelena and Sykes, David B and Hsu, Peggy P and Vander Heiden, Matthew G and Vidoudez, Charles and Sunia A Trauger and Haigis, Marcia C and Scadden, David T}
}
@article {1574867,
	title = {Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer},
	journal = {Nat Commun},
	volume = {11},
	number = {1},
	year = {2020},
	month = {2020 05 11},
	pages = {2350},
	abstract = {BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a~single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.},
	keywords = {Animals, Azepines, Cell Cycle Checkpoints, Cell Proliferation, Clone Cells, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, DNA, Neoplasm, Drug Resistance, Neoplasm, Drug Synergism, Female, Gene Expression Regulation, Neoplastic, Mice, Models, Biological, Mutation, Paclitaxel, Piperazines, Ploidies, Proteins, Pyridines, Retinoblastoma Protein, Treatment Outcome, Triazoles, Triple Negative Breast Neoplasms, Up-Regulation},
	issn = {2041-1723},
	doi = {10.1038/s41467-020-16170-3},
	author = {Ge, Jennifer Y and Shu, Shaokun and Kwon, Mijung and Jovanovi{\'c}, Bojana and Murphy, Katherine and Gulvady, Anushree and Fassl, Anne and Trinh, Anne and Kuang, Yanan and Heavey, Grace A and Luoma, Adrienne and Paweletz, Cloud and Thorner, Aaron R and Wucherpfennig, Kai W and Qi, Jun and Brown, Myles and Sicinski, Piotr and McDonald, Thomas O and Pellman, David and Michor, Franziska and Polyak, Kornelia}
}
@article {1572221,
	title = {PDX-derived organoids model in vivo drug response and secrete biomarkers},
	journal = {JCI Insight},
	volume = {5},
	number = {21},
	year = {2020},
	month = {2020 Nov 05},
	abstract = {Patient-derived organoid models are proving to be a powerful platform for both basic and translational studies. Here we conduct a methodical analysis of pancreatic ductal adenocarcinoma (PDAC) tumor organoid drug response in paired patient-derived xenograft (PDX) and PDX-derived organoid (PXO) models grown under WNT-free culture conditions. We report a specific relationship between area under the curve value of organoid drug dose response and in vivo tumor growth, irrespective of the drug treatment. In addition, we analyzed the glycome of PDX and PXO models and demonstrate that PXOs recapitulate the in vivo glycan landscape. In addition, we identify a core set of 57 N-glycans detected in all 10 models that represent 50\%-94\% of the relative abundance of all N-glycans detected in each of the models. Last, we developed a secreted biomarker discovery pipeline using media supernatant of organoid cultures and identified potentially new extracellular vesicle (EV) protein markers. We validated our findings using plasma samples from patients with PDAC, benign gastrointestinal diseases, and chronic pancreatitis and discovered that 4 EV proteins are potential circulating biomarkers for PDAC. Thus, we demonstrate the utility of organoid cultures to not only model in vivo drug responses but also serve as a powerful platform for discovering clinically actionable serologic biomarkers.},
	issn = {2379-3708},
	doi = {10.1172/jci.insight.135544},
	author = {Huang, Ling and Bockorny, Bruno and Paul, Indranil and Akshinthala, Dipikaa and Frappart, Pierre-Oliver and Gandarilla, Omar and Bose, Arindam and Sanchez-Gonzalez, Veronica and Rouse, Emily E and Lehoux, Sylvain D and Pandell, Nicole and Lim, Christine M and Clohessy, John G and Grossman, Joseph and Gonzalez, Raul and Del Pino, Sofia Perea and Daaboul, George and Sawhney, Mandeep S and Freedman, Steven D and Kleger, Alexander and Cummings, Richard D and Emili, Andrew and Muthuswamy, Lakshmi B and Hidalgo, Manuel and Muthuswamy, Senthil K}
}
@article {1572202,
	title = {Aging-Associated Alterations in Mammary Epithelia and Stroma Revealed by Single-Cell RNA Sequencing},
	journal = {Cell Rep},
	volume = {33},
	number = {13},
	year = {2020},
	month = {2020 12 29},
	pages = {108566},
	abstract = {Aging is closely associated with increased susceptibility to breast cancer, yet there have been limited systematic studies of aging-induced alterations in the mammary gland. Here, we leverage high-throughput single-cell RNA sequencing to generate a detailed transcriptomic atlas of young and aged murine mammary tissues. By analyzing epithelial, stromal, and immune cells, we identify age-dependent alterations in cell proportions and gene expression, providing evidence that suggests alveolar maturation and physiological decline. The analysis also uncovers potential pro-tumorigenic mechanisms coupled to the age-associated loss of tumor suppressor function and change in microenvironment. In addition, we identify a rare, age-dependent luminal population co-expressing hormone-sensing and secretory-alveolar lineage markers, as well as two macrophage populations expressing distinct gene signatures, underscoring the complex heterogeneity of the mammary epithelia and stroma. Collectively, this rich single-cell atlas reveals the effects of aging on mammary physiology and can serve as a useful resource for understanding aging-associated cancer risk.},
	keywords = {Aging, Animals, Biomarkers, Cells, Cultured, Cellular Senescence, Dendritic Cells, Epithelial Cells, Female, Gene Expression Regulation, Genes, Tumor Suppressor, High-Throughput Nucleotide Sequencing, Lymphocytes, Macrophages, Mammary Glands, Animal, Mice, Inbred C57BL, Single-Cell Analysis, Stromal Cells, Transcriptome},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2020.108566},
	author = {Li, Carman Man-Chung and Shapiro, Hana and Tsiobikas, Christina and Selfors, Laura M and Chen, Huidong and Rosenbluth, Jennifer and Moore, Kaitlin and Gupta, Kushali P and Gray, G Kenneth and Oren, Yaara and Steinbaugh, Michael J and Guerriero, Jennifer L and Pinello, Luca and Regev, Aviv and Brugge, Joan S}
}
@article {1572208,
	title = {Comparing the Efficacy of Cancer Therapies between Subgroups in Basket Trials},
	journal = {Cell Syst},
	volume = {11},
	number = {5},
	year = {2020},
	month = {2020 Nov 18},
	pages = {449-460.e2},
	abstract = {The need to test anticancer drugs in multiple indications has been addressed by basket trials, which are Phase I or II clinical trials involving multiple tumor subtypes and a single master protocol. Basket trials typically involve few patients per type, making it challenging to rigorously compare responses across types. We describe the use of permutation testing to test for differences among subgroups using empirical null distributions and the Benjamini-Hochberg procedure to control for false discovery. We apply the approach retrospectively to tumor-volume changes and progression-free survival in published basket trials for neratinib, larotrectinib, pembrolizumab, and imatinib and uncover examples of therapeutic benefit missed by conventional binomial testing. For example, we identify an overlooked opportunity for use of neratinib in lung cancers carrying ERBB2 Exon 20 mutations. Permutation testing can be used to design basket trials but is more conservatively introduced alongside established approaches to enrollment such as Simon{\textquoteright}s two-stage design.},
	issn = {2405-4720},
	doi = {10.1016/j.cels.2020.09.003},
	author = {Palmer, Adam C and Plana, Deborah and Sorger, Peter K}
}
@article {1572210,
	title = {The effects of age and systemic metabolism on anti-tumor T cell responses},
	journal = {Elife},
	volume = {9},
	year = {2020},
	month = {2020 11 10},
	abstract = {Average age and obesity prevalence are increasing globally. Both aging and obesity are characterized by profound systemic metabolic and immunologic changes and are cancer risk factors. The mechanisms linking age and body weight to cancer are incompletely understood, but recent studies have provided evidence that the anti-tumor immune response is reduced in both conditions, while responsiveness to immune checkpoint blockade, a form of cancer immunotherapy, is paradoxically intact. Dietary restriction, which promotes health and lifespan, may enhance cancer immunity. These findings illustrate that the systemic context can impact anti-tumor immunity and immunotherapy responsiveness. Here, we review the current knowledge of how age and systemic metabolic state affect the anti-tumor immune response, with an emphasis on CD8 T cells, which are key players in anti-tumor immunity. A better understanding of the underlying mechanisms may lead to novel therapies enhancing anti-tumor immunity in the context of aging or metabolic dysfunction.},
	issn = {2050-084X},
	doi = {10.7554/eLife.62420},
	author = {Drijvers, Jefte M and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1572199,
	title = {Genomic Alterations during the to Invasive Ductal Breast Carcinoma Transition Shaped by the Immune System},
	journal = {Mol Cancer Res},
	year = {2020},
	month = {2020 Dec 18},
	abstract = {The drivers of ductal carcinoma (DCIS) to invasive ductal carcinoma (IDC) transition are poorly understood. Here, we conducted an integrated genomic, transcriptomic, and whole-slide image analysis to evaluate changes in copy-number profiles, mutational profiles, expression, neoantigen load, and topology in 6 cases of matched pure DCIS and recurrent IDC. We demonstrate through combined copy-number and mutational analysis that recurrent IDC can be genetically related to its pure DCIS despite long latency periods and therapeutic interventions. Immune "hot" and "cold" tumors can arise as early as DCIS and are subtype-specific. Topologic analysis showed a similar degree of pan-leukocyte-tumor mixing in both DCIS and IDC but differ when assessing specific immune subpopulations such as CD4 T cells and CD68 macrophages. Tumor-specific copy-number aberrations in MHC-I presentation machinery and losses in 3p, 4q, and 5p are associated with differences in immune signaling in estrogen receptor (ER)-negative IDC. Common oncogenic hotspot mutations in genes including and are predicted to be neoantigens yet are paradoxically conserved during the DCIS-to-IDC transition, and are associated with differences in immune signaling. We highlight both tumor and immune-specific changes in the transition of pure DCIS to IDC, including genetic changes in tumor cells that may have a role in modulating immune function and assist in immune escape, driving the transition to IDC. IMPLICATIONS: We demonstrate that the to IDC evolutionary bottleneck is shaped by both tumor and immune cells.},
	issn = {1557-3125},
	doi = {10.1158/1541-7786.MCR-20-0949},
	author = {Trinh, Anne and Gil Del Alcazar, Carlos R and Shukla, Sachet A and Chin, Koei and Chang, Young Hwan and Thibault, Guillaume and Eng, Jennifer and Jovanovi{\'c}, Bojana and Aldaz, C Marcelo and Park, So Yeon and Jeong, Joon and Wu, Catherine and Gray, Joe and Polyak, Kornelia}
}
@article {1572207,
	title = {Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer},
	journal = {Breast Cancer Res},
	volume = {22},
	number = {1},
	year = {2020},
	month = {2020 11 30},
	pages = {132},
	abstract = {BACKGROUND: Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC.

METHODS: The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors.

RESULTS: Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2.

CONCLUSIONS: The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies.},
	keywords = {Aniline Compounds, Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, bcl-X Protein, Breast, Drug Resistance, Neoplasm, ErbB Receptors, Female, Humans, Immunoconjugates, Mice, Proto-Oncogene Proteins c-bcl-2, Sulfonamides, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays},
	issn = {1465-542X},
	doi = {10.1186/s13058-020-01374-8},
	author = {Zoeller, Jason J and Vagodny, Aleksandr and Daniels, Veerle W and Taneja, Krishan and Tan, Benjamin Y and DeRose, Yoko S and Fujita, Maihi and Welm, Alana L and Letai, Anthony and Leverson, Joel D and Blot, Vincent and Bronson, Roderick T. and Dillon, Deborah A and Brugge, Joan S}
}
@article {1572203,
	title = {Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity},
	journal = {Cell},
	volume = {183},
	number = {7},
	year = {2020},
	month = {2020 12 23},
	pages = {1848-1866.e26},
	abstract = {Obesity is a major cancer risk factor, but how differences in systemic metabolism change the tumor microenvironment (TME) and impact anti-tumor immunity is not understood. Here, we demonstrate that high-fat diet (HFD)-induced obesity impairs CD8+ T~cell function in the murine TME, accelerating tumor growth. We generate a single-cell resolution atlas of cellular metabolism in the TME, detailing how it changes with diet-induced obesity. We find that tumor and CD8+ T~cells display distinct metabolic adaptations to obesity. Tumor cells increase fat uptake with HFD, whereas tumor-infiltrating CD8+ T~cells do not. These differential adaptations lead to altered fatty acid partitioning in HFD tumors, impairing CD8+ T~cell infiltration and function. Blocking metabolic reprogramming by tumor cells in obese mice improves anti-tumor immunity. Analysis of human cancers reveals similar transcriptional changes in CD8+ T~cell markers, suggesting interventions that exploit metabolism to improve cancer immunotherapy.},
	keywords = {Adiposity, Animals, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cell Proliferation, Diet, High-Fat, Fatty Acids, HEK293 Cells, Humans, Hypoxia-Inducible Factor-Proline Dioxygenases, Immunity, Kinetics, Lymphocytes, Tumor-Infiltrating, Mice, Inbred C57BL, Mice, Knockout, Neoplasms, Obesity, Oxidation-Reduction, Principal Component Analysis, Procollagen-Proline Dioxygenase, Proteomics, Tumor Microenvironment},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2020.11.009},
	author = {Ringel, Alison E and Drijvers, Jefte M and Baker, Gregory J and Catozzi, Alessia and Garc{\'\i}a-Ca{\~n}averas, Juan C and Gassaway, Brandon M and Miller, Brian C and Juneja, Vikram R and Nguyen, Thao H and Joshi, Shakchhi and Yao, Cong-Hui and Yoon, Haejin and Sage, Peter T and LaFleur, Martin W and Trombley, Justin D and Jacobson, Connor A and Maliga, Zoltan and Gygi, Steven P and Sorger, Peter K and Rabinowitz, Joshua D and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1572212,
	title = {Physical traits of cancer},
	journal = {Science},
	volume = {370},
	number = {6516},
	year = {2020},
	month = {2020 10 30},
	abstract = {The role of the physical microenvironment in tumor development, progression, metastasis, and treatment is gaining appreciation. The emerging multidisciplinary field of the physical sciences of cancer is now embraced by engineers, physicists, cell biologists, developmental biologists, tumor biologists, and oncologists attempting to understand how physical parameters and processes affect cancer progression and treatment. Discoveries in this field are starting to be translated into new therapeutic strategies for cancer. In this Review, we propose four physical traits of tumors that contribute to tumor progression and treatment resistance: (i) elevated solid stresses (compression and tension), (ii) elevated interstitial fluid pressure, (iii) altered material properties (for example, increased tissue stiffness, which historically has been used to detect cancer by palpation), and (iv) altered physical microarchitecture. After defining these physical traits, we discuss their causes, consequences, and how they complement the biological hallmarks of cancer.},
	keywords = {Disease Progression, Humans, Mechanical Phenomena, Neoplasms},
	issn = {1095-9203},
	doi = {10.1126/science.aaz0868},
	author = {Nia, Hadi T and Munn, Lance L and Jain, Rakesh K}
}
@article {1572213,
	title = {Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells},
	journal = {Cell Syst},
	volume = {11},
	number = {5},
	year = {2020},
	month = {2020 Nov 18},
	pages = {478-494.e9},
	abstract = {Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAF melanomas, RAF and MEK inhibitors efficiently block oncogenic signaling, but persister cells emerge. Here, we show that persister cells escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors and growth factors operating in an autocrine/paracrine manner. Quantitative proteomics and computational modeling show that ERK pulsing is enabled by rewiring of mitogen-activated protein kinase (MAPK) signaling: from an oncogenic BRAF monomer-driven configuration that is drug sensitive to a receptor-driven configuration that involves Ras-GTP and RAF dimers and is highly resistant to RAF and MEK inhibitors. Altogether, this work shows that pulsatile MAPK activation by factors in the microenvironment generates a persistent population of melanoma cells that rewires MAPK signaling to sustain non-genetic drug resistance.},
	issn = {2405-4720},
	doi = {10.1016/j.cels.2020.10.002},
	author = {Gerosa, Luca and Chidley, Christopher and Fr{\"o}hlich, Fabian and Sanchez, Gabriela and Lim, Sang Kyun and Muhlich, Jeremy and Chen, Jia-Yun and Vallabhaneni, Sreeram and Baker, Gregory J and Schapiro, Denis and Atanasova, Mariya I and Chylek, Lily A and Shi, Tujin and Yi, Lian and Nicora, Carrie D and Claas, Allison and Ng, Thomas Sc and Kohler, Rainer H and Lauffenburger, Douglas A and Weissleder, Ralph and Miller, Miles A and Qian, Wei-jun and Wiley, H Steven and Sorger, Peter K}
}
@article {1572209,
	title = {A Switch in p53 Dynamics Marks Cells That Escape from DSB-Induced Cell Cycle Arrest},
	journal = {Cell Rep},
	volume = {33},
	number = {6},
	year = {2020},
	month = {2020 Nov 10},
	pages = {108392},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2020.108392},
	author = {Tsabar, Michael and Mock, Caroline S and Venkatachalam, Veena and Reyes, Jose and Karhohs, Kyle W and Oliver, Trudy G and Regev, Aviv and Jambhekar, Ashwini and Lahav, Galit}
}
@article {1572205,
	title = {TGFβ: Protecting PD-1 from mRNA Decay},
	journal = {Cancer Immunol Res},
	volume = {8},
	number = {12},
	year = {2020},
	month = {2020 Dec},
	pages = {1464},
	abstract = {Coordinated regulation of genes is key to determining cell fate. Although this is best understood for master regulator transcription factors, posttranscriptional regulation of mRNA stability and nuclear export can be equally effective at altering gene expression. Indeed, the heterogeneity of RNA-binding proteins and miRNAs suggests a deep complexity to posttranscriptional regulatory processes. In this issue, Wu and colleagues report a new mechanism for TGFβ-mediated immune suppression via regulation of mRNA-binding proteins in CD8 T cells..},
	issn = {2326-6074},
	doi = {10.1158/2326-6066.CIR-20-0881},
	author = {Dougan, Stephanie K}
}
@article {1514697,
	title = {High-throughput dynamic BH3 profiling may quickly and accurately predict effective therapies in solid tumors},
	journal = {Sci Signal},
	volume = {13},
	number = {636},
	year = {2020},
	month = {2020 Jun 16},
	abstract = {Despite decades of effort, the sensitivity of patient tumors to individual drugs is often not predictable on the basis of molecular markers alone. Therefore, unbiased, high-throughput approaches to match patient tumors to effective drugs, without requiring a priori molecular hypotheses, are critically needed. Here, we improved upon a method that we previously reported and developed called high-throughput dynamic BH3 profiling (HT-DBP). HT-DBP is a microscopy-based, single-cell resolution assay that enables chemical screens of hundreds to thousands of candidate drugs on freshly isolated tumor cells. The method identifies chemical inducers of mitochondrial apoptotic signaling, a mechanism of cell death. HT-DBP requires only 24 hours of ex vivo culture, which enables a more immediate study of fresh primary tumor cells and minimizes adaptive changes that occur with prolonged ex vivo culture. Effective compounds identified by HT-DBP induced tumor regression in genetically engineered and patient-derived xenograft (PDX) models of breast cancer. We additionally found that chemical vulnerabilities changed as cancer cells expanded ex vivo. Furthermore, using PDX models of colon cancer and resected tumors from colon cancer patients, our data demonstrated that HT-DBP could be used to generate personalized pharmacotypes. Thus, HT-DBP appears to be an ex vivo functional method with sufficient scale to simultaneously function as a companion diagnostic, therapeutic personalization, and discovery tool.},
	issn = {1937-9145},
	doi = {10.1126/scisignal.aay1451},
	author = {Bhola, Patrick D and Ahmed, Eman and Guerriero, Jennifer L and Sicinska, Ewa and Su, Emily and Lavrova, Elizaveta and Ni, Jing and Chipashvili, Otari and Hagan, Timothy and Pioso, Marissa S and McQueeney, Kelley and Ng, Kimmie and Aguirre, Andrew J and Cleary, James M and Cocozziello, David and Sotayo, Alaba and Ryan, Jeremy and Zhao, Jean J and Letai, Anthony}
}
@article {1514699,
	title = {The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution},
	journal = {Cell},
	volume = {181},
	number = {2},
	year = {2020},
	month = {2020 Apr 16},
	pages = {236-249},
	abstract = {Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2020.03.053},
	author = {Rozenblatt-Rosen, Orit and Regev, Aviv and Oberdoerffer, Philipp and Nawy, Tal and Hupalowska, Anna and Rood, Jennifer E and Ashenberg, Orr and Cerami, Ethan and Coffey, Robert J and Demir, Emek and Ding, Li and Esplin, Edward D and Ford, James M and Goecks, Jeremy and Ghosh, Sharmistha and Gray, Joe W and Guinney, Justin and Hanlon, Sean E and Hughes, Shannon K and Hwang, E Shelley and Iacobuzio-Donahue, Christine A and Jan{\'e}-Valbuena, Judit and Johnson, Bruce E and Lau, Ken S and Lively, Tracy and Mazzilli, Sarah A and Pe{\textquoteright}er, Dana and Santagata, Sandro and Shalek, Alex K and Schapiro, Denis and Snyder, Michael P and Sorger, Peter K and Spira, Avrum E and Srivastava, Sudhir and Tan, Kai and West, Robert B and Williams, Elizabeth H and Human Tumor Atlas Network}
}
@article {1514701,
	title = {Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance},
	journal = {Cancer Cell},
	volume = {37},
	number = {4},
	year = {2020},
	month = {2020 Apr 13},
	pages = {471-484},
	abstract = {Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity.},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2020.03.007},
	author = {Marusyk, Andriy and Janiszewska, Michalina and Polyak, Kornelia}
}
@article {1514703,
	title = {Lipid availability determines fate of skeletal progenitor cells via SOX9},
	journal = {Nature},
	volume = {579},
	number = {7797},
	year = {2020},
	month = {2020 03},
	pages = {111-117},
	abstract = {The avascular nature of cartilage makes it a unique tissue, but whether and how the absence of nutrient supply regulates chondrogenesis remain unknown. Here we show that obstruction of vascular invasion during bone healing favours chondrogenic over osteogenic differentiation of skeletal progenitor cells. Unexpectedly, this process is driven by a decreased availability of extracellular lipids. When lipids are scarce, skeletal progenitors activate forkhead box O (FOXO) transcription factors, which bind to the Sox9 promoter and increase its expression. Besides initiating chondrogenesis, SOX9 acts as a regulator of cellular metabolism by suppressing oxidation of fatty acids, and thus adapts the cells to an avascular life. Our results define lipid scarcity as an important determinant of chondrogenic commitment, reveal a role for FOXO transcription factors during lipid starvation, and identify SOX9 as a critical metabolic mediator. These data highlight the importance of the nutritional microenvironment in the specification of skeletal cell fate.},
	keywords = {Animals, Bone and Bones, Cellular Microenvironment, Chondrocytes, Chondrogenesis, Fatty Acids, Female, Food Deprivation, Forkhead Transcription Factors, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Osteogenesis, Oxidation-Reduction, Signal Transduction, SOX9 Transcription Factor, Stem Cells, Wound Healing},
	issn = {1476-4687},
	doi = {10.1038/s41586-020-2050-1},
	author = {van Gastel, Nick and Stegen, Steve and Eelen, Guy and Schoors, Sandra and Carlier, Aur{\'e}lie and Dani{\"e}ls, Veerle W and Baryawno, Ninib and Przybylski, Dariusz and Depypere, Maarten and Stiers, Pieter-Jan and Lambrechts, Dennis and Van Looveren, Riet and Torrekens, Sophie and Sharda, Azeem and Agostinis, Patrizia and Lambrechts, Diether and Maes, Frederik and Swinnen, Johan V and Geris, Liesbet and Van Oosterwyck, Hans and Thienpont, Bernard and Carmeliet, Peter and Scadden, David T and Carmeliet, Geert}
}
@article {1514700,
	title = {Mechanisms generating cancer genome complexity from a single cell division error},
	journal = {Science},
	volume = {368},
	number = {6488},
	year = {2020},
	month = {2020 04 17},
	abstract = {The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. We explain this association by elucidating a mutational cascade that is triggered by a single cell division error-chromosome bridge formation-that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA. A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers.},
	keywords = {Actomyosin, Carcinogenesis, Cell Line, Tumor, Chromosome Breakage, DNA Damage, Exodeoxyribonucleases, Gene Dosage, Genome, Human, Humans, Mechanical Phenomena, Mitosis, Mutagenesis, Mutation, Neoplasms, Phosphoproteins, Single-Cell Analysis},
	issn = {1095-9203},
	doi = {10.1126/science.aba0712},
	author = {Umbreit, Neil T and Zhang, Cheng-Zhong and Lynch, Luke D and Blaine, Logan J and Cheng, Anna M and Tourdot, Richard and Sun, Lili and Almubarak, Hannah F and Judge, Kim and Mitchell, Thomas J and Spektor, Alexander and Pellman, David}
}
@article {1514702,
	title = {Response and mechanisms of resistance to larotrectinib and selitrectinib in metastatic undifferentiated sarcoma harboring oncogenic fusion of NTRK1},
	journal = {JCO Precis Oncol},
	volume = {4},
	year = {2020},
	month = {2020},
	pages = {79-90},
	issn = {2473-4284},
	doi = {10.1200/po.19.00287},
	author = {Hemming, Matthew L and Nathenson, Michael J and Lin, Jia-Ren and Mei, Shaolin and Du, Ziming and Malik, Karan and Marino-Enriquez, Adrian and Jagannathan, Jyothi P and Sorger, Peter K and Bertagnolli, Monica and Sicinska, Ewa and Demetri, George D and Santagata, Sandro}
}
@article {1514696,
	title = {A single-cell landscape of high-grade serous ovarian cancer},
	journal = {Nat Med},
	year = {2020},
	month = {2020 Jun 22},
	abstract = {Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape and provides a resource for the development of novel therapeutic approaches.},
	issn = {1546-170X},
	doi = {10.1038/s41591-020-0926-0},
	author = {Izar, Benjamin and Itay Tirosh and Stover, Elizabeth H and Wakiro, Isaac and Cuoco, Michael S and Alter, Idan and Rodman, Christopher and Leeson, Rachel and Su, Mei-Ju and Shah, Parin and Iwanicki, Marcin and Walker, Sarah R and Kanodia, Abhay and Melms, Johannes C and Mei, Shaolin and Lin, Jia-Ren and Porter, Caroline B M and Slyper, Michal and Waldman, Julia and Jerby-Arnon, Livnat and Ashenberg, Orr and Brinker, Titus J and Mills, Caitlin and Rogava, Meri and Vigneau, S{\'e}bastien and Sorger, Peter K and Garraway, Levi A and Konstantinopoulos, Panagiotis A and Liu, Joyce F and Matulonis, Ursula and Johnson, Bruce E and Rozenblatt-Rosen, Orit and Rotem, Asaf and Regev, Aviv}
}
@article {1514698,
	title = {Synthetic Lethal and Resistance Interactions with BET Bromodomain Inhibitors in Triple-Negative Breast Cancer},
	journal = {Mol Cell},
	volume = {78},
	number = {6},
	year = {2020},
	month = {2020 06 18},
	pages = {1096-1113.e8},
	abstract = {BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents. We also uncovered functional similarities and differences among BRD2, BRD4, and BRD7. Although deletion of BRD2 enhances sensitivity to BBDIs, BRD7 loss leads to gain of TEAD-YAP chromatin binding and luminal features associated with BBDI resistance. Single-cell RNA-seq, ATAC-seq, and cellular barcoding analysis of BBDI responses in sensitive and resistant cell lines highlight significant heterogeneity among samples and demonstrate that BBDI resistance can be pre-existing or acquired.},
	keywords = {Animals, Antineoplastic Agents, Azepines, Cell Cycle Proteins, Cell Line, Tumor, Chromosomal Proteins, Non-Histone, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Mice, Mice, Inbred NOD, Nuclear Proteins, Proteins, Signal Transduction, Transcription Factors, Triazoles, Triple Negative Breast Neoplasms},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2020.04.027},
	author = {Shu, Shaokun and Wu, Hua-Jun and Ge, Jennifer Y and Zeid, Rhamy and Harris, Isaac S and Jovanovi{\'c}, Bojana and Murphy, Katherine and Wang, Binbin and Qiu, Xintao and Endress, Jennifer E and Reyes, Jaime and Lim, Klothilda and Font-Tello, Alba and Syamala, Sudeepa and Xiao, Tengfei and Reddy Chilamakuri, Chandra Sekhar and Papachristou, Evangelia K and D{\textquoteright}Santos, Clive and Anand, Jayati and Hinohara, Kunihiko and Li, Wei and McDonald, Thomas O and Luoma, Adrienne and Modiste, Rebecca J and Nguyen, Quang-De and Michel, Brittany and Cejas, Paloma and Kadoch, Cigall and Jaffe, Jacob D and Wucherpfennig, Kai W and Qi, Jun and Liu, X Shirley and Long, Henry and Brown, Myles and Carroll, Jason S and Brugge, Joan S and Bradner, James and Michor, Franziska and Polyak, Kornelia}
}
@article {1514679,
	title = {The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple Negative Breast Cancer},
	journal = {Cancer Discovery},
	year = {2020},
	author = {Liu, H and Paddock, MN and Wang H}
}
@article {1504683,
	title = {A Deregulated HOX Gene Axis Confers an Epigenetic Vulnerability in KRAS-Mutant Lung Cancers},
	journal = {Cancer Cell},
	year = {2020},
	month = {2020 Mar 19},
	abstract = {While KRAS mutations are common in non-small cell lung cancer (NSCLC), effective treatments are lacking. Here, we report that half of KRAS-mutant NSCLCs aberrantly express the homeobox protein HOXC10, largely due to unappreciated defects in PRC2, which confers sensitivity to combined BET/MEK inhibitors in xenograft and PDX models. Efficacy of the combination is dependent on suppression of HOXC10 by BET inhibitors. We further show that HOXC10 regulates the expression of pre-replication complex (pre-RC) proteins in sensitive tumors. Accordingly, BET/MEK inhibitors suppress pre-RC proteins in cycling cells, triggering stalled replication, DNA damage, and death. These studies reveal a promising therapeutic strategy for KRAS-mutant NSCLCs, identify a predictive biomarker of response, and define a subset of NSCLCs with a targetable epigenetic vulnerability.},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2020.03.004},
	author = {Guerra, Stephanie L and Maertens, Oph{\'e}lia and Kuzmickas, Ryan and De Raedt, Thomas and Adeyemi, Richard O and Guild, Caroline J and Guillemette, Shawna and Redig, Amanda J and Chambers, Emily S and Xu, Man and Tiv, Hong and Santagata, Sandro and J{\"a}nne, Pasi A and Elledge, Stephen J and Cichowski, Karen}
}
@article {1504681,
	title = {Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer},
	journal = {Nat Commun},
	volume = {11},
	number = {1},
	year = {2020},
	month = {2020 Mar 19},
	pages = {1459},
	abstract = {Combined PARP and immune checkpoint inhibition has yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking. We performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer\&nbsp;(NCT02657889). We identify two determinants of response; mutational signature 3 reflecting defective homologous recombination DNA repair, and positive immune score as a surrogate of interferon-primed exhausted CD8 + T-cells in the tumor microenvironment. Presence of one or both features associates with an improved outcome while concurrent absence yields no responses. Single-cell spatial analysis reveals prominent interactions of exhausted CD8 + T-cells and PD-L1 + macrophages and PD-L1 + tumor cells as mechanistic determinants of response. Furthermore, spatial analysis of two extreme responders shows differential clustering of exhausted CD8 + T-cells with PD-L1 + macrophages in the first, and exhausted CD8 + T-cells with cancer cells harboring genomic PD-L1 and PD-L2 amplification in the second.},
	issn = {2041-1723},
	doi = {10.1038/s41467-020-15315-8},
	author = {F{\"a}rkkil{\"a}, Anniina and Gulhan, Doga C and Casado, Julia and Jacobson, Connor A and Nguyen, Huy and Kochupurakkal, Bose and Maliga, Zoltan and Yapp, Clarence and Chen, Yu-An and Schapiro, Denis and Zhou, Yinghui and Graham, Julie R and Dezube, Bruce J and Munster, Pamela and Santagata, Sandro and Garcia, Elizabeth and Rodig, Scott and Lako, Ana and Chowdhury, Dipanjan and Shapiro, Geoffrey I and Matulonis, Ursula A and Park, Peter J and Hautaniemi, Sampsa and Sorger, Peter K and Swisher, Elizabeth M and D{\textquoteright}Andrea, Alan D and Konstantinopoulos, Panagiotis A}
}
@article {1484512,
	title = {HSF1 phase transition mediates stress adaptation and cell fate decisions},
	journal = {Nat Cell Biol},
	year = {2020},
	month = {2020 Feb 03},
	abstract = {Under proteotoxic stress, some cells survive whereas others die. The mechanisms governing this heterogeneity in cell fate remain unknown. Here we report that condensation and phase transition of heat-shock factor 1 (HSF1), a transcriptional regulator of chaperones, is integral to cell-fate decisions underlying survival or death. During stress, HSF1 drives chaperone expression but also accumulates separately in nuclear stress bodies called foci. Foci formation has been regarded as a marker of cells actively upregulating chaperones. Using multiplexed tissue imaging, we observed HSF1 foci in human tumours. Paradoxically, their presence inversely correlated with chaperone expression. By live-cell microscopy and single-cell analysis, we found that foci dissolution rather than formation promoted HSF1 activity and cell survival. During prolonged stress, the biophysical properties of HSF1 foci changed; small, fluid condensates enlarged into indissoluble gel-like arrangements with immobilized HSF1. Chaperone gene induction was reduced in such cells, which were prone to apoptosis. Quantitative analysis suggests that survival under stress results from competition between concurrent but opposing mechanisms. Foci may serve as sensors that tune cytoprotective responses, balancing rapid transient responses and irreversible outcomes.},
	issn = {1476-4679},
	doi = {10.1038/s41556-019-0458-3},
	author = {Gaglia, Giorgio and Rashid, Rumana and Yapp, Clarence and Joshi, Gaurav N and Li, Carmen G and Lindquist, Susan L and Sarosiek, Kristopher A and Whitesell, Luke and Sorger, Peter K and Santagata, Sandro}
}
@article {1504682,
	title = {MAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in -, and -Mutant Melanomas},
	journal = {Cancer Discov},
	volume = {9},
	number = {4},
	year = {2019},
	month = {2019 04},
	pages = {526-545},
	abstract = {Although the majority of -mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in - and -mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three RAS pathway-driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, in both models that are sensitive or relatively resistant to these agents. Interestingly, expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, addition of entinostat triggers the concomitant suppression of nonhomologous end-joining genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together, these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker. SIGNIFICANCE: BRAF/MEK inhibitors are not typically curative in -mutant melanomas and are ineffective in - and -mutant tumors. We show that HDAC inhibitors dramatically enhance the efficacy of BRAF/MEK inhibitors in sensitive and insensitive RAS pathway-driven melanomas by coordinately suppressing two DNA repair pathways, and identify a clinical biomarker that predicts responsiveness...},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-18-0879},
	author = {Maertens, Oph{\'e}lia and Kuzmickas, Ryan and Manchester, Haley E and Emerson, Chloe E and Gavin, Alessandra G and Guild, Caroline J and Wong, Terence C and De Raedt, Thomas and Bowman-Colin, Christian and Hatchi, Elodie and Garraway, Levi A and Flaherty, Keith T and Pathania, Shailja and Elledge, Stephen J and Cichowski, Karen}
}
@article {1476435,
	title = {PARP Inhibitor Efficacy Depends on CD8 T-cell Recruitment via Intratumoral STING Pathway Activation in BRCA-Deficient Models of Triple-Negative Breast Cancer},
	journal = {Cancer Discov},
	volume = {9},
	number = {6},
	year = {2019},
	month = {2019 Jun},
	pages = {722-737},
	abstract = {Combinatorial clinical trials of PARP inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP inhibitor olaparib induces CD8 T-cell infiltration and activation , and that CD8 T-cell depletion severely compromises antitumor efficacy. Olaparib-induced T-cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-deficient compared with HR-proficient TNBC cells and models. CRISPR-mediated knockout of STING in cancer cells prevents proinflammatory signaling and is sufficient to abolish olaparib-induced T-cell infiltration . These findings elucidate an additional mechanism of action of PARP inhibitors and provide a rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. SIGNIFICANCE: This work demonstrates cross-talk between PARP inhibition and the tumor microenvironment related to STING/TBK1/IRF3 pathway activation in cancer cells that governs CD8 T-cell recruitment and antitumor efficacy. The data provide insight into the mechanism of action of PARP inhibitors in -associated breast cancer..},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-18-1218},
	author = {Pantelidou, Constantia and Sonzogni, Olmo and De Oliveria Taveira, Mateus and Mehta, Anita K and Kothari, Aditi and Wang, Dan and Visal, Tanvi and Li, Michelle K and Pinto, Jocelin and Castrillon, Jessica A and Cheney, Emily M and Bouwman, Peter and Jonkers, Jos and Rottenberg, Sven and Guerriero, Jennifer L and Wulf, Gerburg M and Shapiro, Geoffrey I}
}
@article {1476434,
	title = {A curative combination cancer therapy achieves high fractional cell killing through low cross-resistance and drug additivity},
	journal = {Elife},
	volume = {8},
	year = {2019},
	month = {2019 11 19},
	abstract = {Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here, we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R-CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R-CHOP exhibit very low cross-resistance but not synergistic interaction: together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50 year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.},
	issn = {2050-084X},
	doi = {10.7554/eLife.50036},
	author = {Palmer, Adam C and Chidley, Christopher and Sorger, Peter K}
}
@article {1476433,
	title = {Torin2 Exploits Replication and Checkpoint Vulnerabilities to Cause Death of PI3K-Activated Triple-Negative Breast Cancer Cells},
	journal = {Cell Syst},
	year = {2019},
	month = {2019 Dec 02},
	abstract = {Frequent mutation of PI3K/AKT/mTOR signaling pathway genes in human cancers has stimulated large investments in targeted drugs but clinical successes are rare. As a result, many cancers with high PI3K pathway activity, such as triple-negative breast cancer (TNBC), are treated primarily with chemotherapy. By systematically analyzing responses of TNBC cells to a diverse collection of PI3K pathway inhibitors, we find that one drug, Torin2, is unusually effective because it inhibits both mTOR and other PI3K-like kinases (PIKKs). In contrast to mTOR-selective inhibitors, Torin2 exploits dependencies on several kinases for S-phase progression and cell-cycle checkpoints, thereby causing accumulation of single-stranded DNA and death by replication catastrophe or mitotic failure. Thus, Torin2 and its chemical analogs represent a mechanistically distinct class of PI3K pathway inhibitors that are uniquely cytotoxic to TNBC cells. This insight could be translated therapeutically by further developing Torin2 analogs or combinations of existing mTOR and PIKK inhibitors.},
	issn = {2405-4720},
	doi = {10.1016/j.cels.2019.11.001},
	author = {Chopra, Sameer S and Jenney, Anne and Palmer, Adam and Niepel, Mario and Chung, Mirra and Mills, Caitlin and Sivakumaren, Sindhu Carmen and Liu, Qingsong and Chen, Jia-Yun and Yapp, Clarence and Asara, John M and Gray, Nathanael S and Sorger, Peter K}
}
@article {1469184,
	title = {Acquired Resistance Is Oncogene and Drug Agnostic},
	journal = {Cancer Cell},
	volume = {36},
	number = {4},
	year = {2019},
	month = {2019 Oct 14},
	pages = {347-349},
	abstract = {Recent approvals of TRK inhibitors have demonstrated the success of a tumor agnostic approach to oncogene-targeted therapy across cancers. Collective data from acquired resistance studies suggest that resistance mechanisms, which include both kinase domain mutations and bypass signaling via RTK-RAS-RAF-MAPK pathways, frequently recur regardless of tumor type, oncogene, and drug.},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2019.09.011},
	author = {Doebele, Robert C}
}
@article {1469183,
	title = {DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance},
	journal = {J Clin Invest},
	year = {2019},
	month = {2019 Oct 14},
	abstract = {The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp{\textquoteright}s ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.},
	issn = {1558-8238},
	doi = {10.1172/JCI128571},
	author = {Togami, Katsuhiro and Pastika, Timothy and Stephansky, Jason and Ghandi, Mahmoud and Christie, Amanda L and Jones, Kristen L and Johnson, Carl A and Lindsay, Ross W and Brooks, Christopher L and Letai, Anthony and Craig, Jeffrey W and Pozdnyakova, Olga and Weinstock, David M and Montero, Joan and Aster, Jon C and Johannessen, Cory M and Lane, Andrew A}
}
@article {1469181,
	title = {Functional profiling of nucleotide Excision repair in breast cancer},
	journal = {DNA Repair (Amst)},
	volume = {82},
	year = {2019},
	month = {2019 Oct},
	pages = {102697},
	abstract = {Homologous recombination deficiency conferred by alterations in BRCA1 or BRCA2 are common in breast tumors and can drive sensitivity to platinum chemotherapy and PARP inhibitors. Alterations in nucleotide excision repair (NER) activity can also impact sensitivity to DNA damaging agents, but NER activity in breast cancer has been poorly characterized. Here, we apply a novel immunofluorescence-based cellular NER assay to screen a large panel of breast epithelial and cancer cell lines. Although the majority of breast cancer models are NER proficient, we identify an example of a breast cancer cell line with profound NER deficiency. We show that NER deficiency in this model is driven by epigenetic silencing of the ERCC4 gene, leading to lack of expression of the NER nuclease XPF, and that ERCC4 methylation is also strongly correlated with ERCC4 mRNA and XPF protein expression in primary breast tumors. Re-expression of XPF in the ERCC4-deficient breast cancer rescues NER deficiency and cisplatin sensitivity, but does not impact PARP inhibitor sensitivity. These findings demonstrate the potential to use functional assays to identify novel mechanisms of DNA repair deficiency and nominate NER deficiency as a platinum sensitivity biomarker in breast cancer.},
	issn = {1568-7856},
	doi = {10.1016/j.dnarep.2019.102697},
	author = {Rajkumar-Calkins, Anne S and Szalat, Raphael and Dreze, Matija and Khan, Iman and Frazier, Zo{\"e} and Reznichenkov, Elizaveta and Schnorenberg, Mathew R and Tsai, Yi-Fang and Nguyen, Huy and Kochupurakkal, Bose and D{\textquoteright}Andrea, Alan D and Shapiro, Geoffrey I and Lazaro, Jean-Bernard and Mouw, Kent W}
}
@article {1469174,
	title = {High-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program},
	journal = {Nat Commun},
	volume = {10},
	number = {1},
	year = {2019},
	month = {2019 Sep 25},
	pages = {4358},
	abstract = {Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-12298-z},
	author = {Labb{\'e}, David P and Zadra, Giorgia and Yang, Meng and Reyes, Jaime M and Lin, Charles Y and Cacciatore, Stefano and Ebot, Ericka M and Creech, Amanda L and Giunchi, Francesca and Fiorentino, Michelangelo and Elfandy, Habiba and Syamala, Sudeepa and Karoly, Edward D and Alshalalfa, Mohammed and Erho, Nicholas and Ross, Ashley and Schaeffer, Edward M and Gibb, Ewan A and Takhar, Mandeep and Den, Robert B and Lehrer, Jonathan and Karnes, R Jeffrey and Freedland, Stephen J and Davicioni, Elai and Spratt, Daniel E and Ellis, Leigh and Jaffe, Jacob D and D'Amico, Anthony V and Kantoff, Philip W and Bradner, James E and Mucci, Lorelei A and Chavarro, Jorge E and Loda, Massimo and Brown, Myles}
}
@article {1469176,
	title = {miR-147b-mediated TCA cycle dysfunction and pseudohypoxia initiate drug tolerance to EGFR inhibitors in lung adenocarcinoma},
	journal = {Nat Metab},
	volume = {1},
	number = {4},
	year = {2019},
	month = {2019 Apr},
	pages = {460-474},
	abstract = {Drug-tolerance is an acute defense response prior to a fully drug-resistant state and tumor relapse, however there are few therapeutic agents targeting drug-tolerance in the clinic. Here we show that miR-147b initiates a reversible tolerant-state to the EGFR inhibitor osimertinib in non-small cell lung cancer. With miRNA-seq analysis we find that miR-147b is the most upregulated microRNA in osimertinib-tolerant and mutated lung cancer cells. Whole transcriptome analysis of single-cell derived clones reveals a link between osimertinib-tolerance and pseudohypoxia responses irrespective of oxygen levels. Further metabolomics and genetic studies demonstrate that osimertinib-tolerance is driven by miR-147b repression of VHL and succinate dehydrogenase linked to the tricarboxylic acid cycle and pseudohypoxia pathways. Finally, pretreatment with a miR-147b inhibitor delays osimertinib-associated drug tolerance in patient-derived three-dimensional (3D) structures. This link between miR-147b and tricarboxylic acid cycle may provide promising targets for preventing tumor relapse.},
	issn = {2522-5812},
	doi = {10.1038/s42255-019-0052-9},
	author = {Zhang, Wen Cai and Wells, Julie M and Chow, Kin-Hoe and Huang, He and Yuan, Min and Saxena, Tanvi and Melnick, Mary Ann and Politi, Katerina and Asara, John M and Costa, Daniel B and Bult, Carol J and Slack, Frank J}
}
@article {1469175,
	title = {Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies},
	journal = {Cancer Cell},
	volume = {36},
	number = {4},
	year = {2019},
	month = {2019 Oct 14},
	pages = {369-384.e13},
	abstract = {Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B\&nbsp;cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy\&nbsp;with metabolic modulators to address venetoclax resistance.},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2019.08.005},
	author = {Gui{\`e}ze, Romain and Liu, Vivian M and Rosebrock, Daniel and Jourdain, Alexis A and Hern{\'a}ndez-S{\'a}nchez, Mar{\'\i}a and Martinez Zurita, Aina and Sun, Jing and Ten Hacken, Elisa and Baranowski, Kaitlyn and Thompson, Philip A and Heo, Jin-Mi and Cartun, Zachary and Ayg{\"u}n, Ozan and Iorgulescu, J Bryan and Zhang, Wandi and Notarangelo, Giulia and Livitz, Dimitri and Li, Shuqiang and Davids, Matthew S and Biran, Anat and Fernandes, Stacey M and Brown, Jennifer R and Lako, Ana and Ciantra, Zoe B and Lawlor, Matthew A and Keskin, Derin B and Udeshi, Namrata D and Wierda, William G and Livak, Kenneth J and Letai, Anthony G and Neuberg, Donna and Harper, J Wade and Carr, Steven A and Piccioni, Federica and Ott, Christopher J and Leshchiner, Ignaty and Johannessen, Cory M and Doench, John and Mootha, Vamsi K and Getz, Gad and Wu, Catherine J}
}
@article {1469180,
	title = {Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ},
	journal = {Nat Commun},
	volume = {10},
	number = {1},
	year = {2019},
	month = {2019 Sep 13},
	pages = {4182},
	abstract = {Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63TCF7 myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63TCF7 myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-12125-5},
	author = {Ding, Lina and Su, Ying and Fassl, Anne and Hinohara, Kunihiko and Qiu, Xintao and Harper, Nicholas W and Jin Huh, Sung and Bloushtain-Qimron, Noga and Jovanovi{\'c}, Bojana and Ekram, Muhammad and Zi, Xiaoyuan and Hines, William C and Ale{\v c}kovi{\'c}, Ma{\v s}a and Del Alcazar, Carlos Gil and Caulfield, Ryan J and Bonal, Dennis M and Nguyen, Quang-De and Merino, Vanessa F and Choudhury, Sibgat and Ethington, Gabrielle and Panos, Laura and Grant, Michael and Herlihy, William and Au, Alfred and Rosson, Gedge D and Argani, Pedram and Richardson, Andrea L and Dillon, Deborah and Allred, D Craig and Babski, Kirsten and Min Hui Kim, Elizabeth and McDonnell, Charles H and Wagner, Jon and Rowberry, Ron and Bobolis, Kristie and Kleer, Celina G and Hwang, E Shelley and Blum, Joanne L and Cristea, Simona and Sicinski, Piotr and Fan, Rong and Long, Henry W and Sukumar, Saraswati and Park, So Yeon and Garber, Judy E and Bissell, Mina and Yao, Jun and Polyak, Kornelia}
}
@article {1469182,
	title = {Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer},
	journal = {Mol Cancer Res},
	year = {2019},
	month = {2019 Aug 28},
	abstract = {High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including (BCL-XL) and (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.},
	issn = {1557-3125},
	doi = {10.1158/1541-7786.MCR-18-1243},
	author = {Stover, Elizabeth H and Baco, Maria B and Cohen, Ofir and Li, Yvonne Y and Christie, Elizabeth L and Bagul, Mukta and Goodale, Amy and Lee, Yenarae and Pantel, Sasha and Rees, Matthew G and Wei, Guo and Presser, Adam G and Gelbard, Maya K and Zhang, Weiqun and Zervantonakis, Ioannis K and Bhola, Patrick D and Ryan, Jeremy and Guerriero, Jennifer L and Montero, Joan and Liang, Felice J and Cherniack, Andrew D and Piccioni, Federica and Matulonis, Ursula A and Bowtell, David D L and Sarosiek, Kristopher A and Letai, Anthony and Garraway, Levi A and Johannessen, Cory M and Meyerson, Matthew}
}
@article {1469179,
	title = {PTPN2 regulates the generation of exhausted CD8 T cell subpopulations and restrains tumor immunity},
	journal = {Nat Immunol},
	volume = {20},
	number = {10},
	year = {2019},
	month = {2019 Oct},
	pages = {1335-1347},
	abstract = {CD8 T cell exhaustion is a state of dysfunction acquired in chronic viral infection and cancer, characterized by the formation of Slamf6 progenitor exhausted and Tim-3 terminally exhausted subpopulations through unknown mechanisms. Here we establish the phosphatase PTPN2 as a new regulator of the differentiation of the terminally exhausted subpopulation that functions by attenuating type 1 interferon signaling. Deletion of Ptpn2 in CD8 T cells increased the generation, proliferative capacity and cytotoxicity of Tim-3 cells without altering Slamf6 numbers during lymphocytic choriomeningitis virus clone 13 infection. Likewise, Ptpn2 deletion in CD8 T cells enhanced Tim-3 anti-tumor responses and improved tumor control. Deletion of Ptpn2 throughout the immune system resulted in MC38 tumor clearance and improved programmed cell death-1 checkpoint blockade responses to B16 tumors. Our results indicate that increasing the number of cytotoxic Tim-3CD8 T cells can promote effective anti-tumor immunity and implicate PTPN2 in immune cells as an attractive cancer immunotherapy target.},
	issn = {1529-2916},
	doi = {10.1038/s41590-019-0480-4},
	author = {LaFleur, Martin W and Nguyen, Thao H and Coxe, Matthew A and Miller, Brian C and Yates, Kathleen B and Gillis, Jacob E and Sen, Debattama R and Gaudiano, Emily F and Abosy, Rose Al and Freeman, Gordon J and Haining, W Nicholas and Sharpe, Arlene H}
}
@article {1469177,
	title = {Qualifying antibodies for image-based immune profiling and multiplexed tissue imaging},
	journal = {Nat Protoc},
	volume = {14},
	number = {10},
	year = {2019},
	month = {2019 Oct},
	pages = {2900-2930},
	abstract = {Multiplexed tissue imaging enables precise, spatially resolved enumeration and characterization of cell types and states in human resection specimens. A growing number of methods applicable to formalin-fixed, paraffin-embedded (FFPE) tissue sections have been described, the majority of which rely on antibodies for antigen detection and mapping. This protocol provides step-by-step procedures for confirming the selectivity and specificity of antibodies used in fluorescence-based tissue imaging and for the construction and validation of antibody panels. Although the protocol is implemented using tissue-based cyclic immunofluorescence (t-CyCIF) as an imaging platform, these antibody-testing methods are broadly applicable. We demonstrate assembly of a 16-antibody panel for enumerating and localizing T cells and B cells, macrophages, and cells expressing immune checkpoint regulators. The protocol is accessible to individuals with experience in microscopy and immunofluorescence; some experience in computation is required for data analysis. A typical 30-antibody dataset for 20 FFPE slides can be generated within 2 weeks.},
	issn = {1750-2799},
	doi = {10.1038/s41596-019-0206-y},
	author = {Du, Ziming and Lin, Jia-Ren and Rashid, Rumana and Maliga, Zoltan and Wang, Shu and Aster, Jon C and Izar, Benjamin and Sorger, Peter K and Santagata, Sandro}
}
@article {1469178,
	title = {T Cell Activation Depends on Extracellular Alanine},
	journal = {Cell Rep},
	volume = {28},
	number = {12},
	year = {2019},
	month = {2019 Sep 17},
	pages = {3011-3021.e4},
	abstract = {T cell stimulation is metabolically demanding. To exit quiescence, T\&nbsp;cells rely on environmental nutrients, including glucose and the amino acids glutamine, leucine, serine, and arginine. The expression of transporters for these nutrients is tightly regulated and required for T\&nbsp;cell activation. In contrast to these amino acids, which are essential or require multi-step biosynthesis, alanine can be made from pyruvate by a single transamination. Here, we show that extracellular alanine is nevertheless required for efficient exit from quiescence during naive T\&nbsp;cell activation and memory T\&nbsp;cell restimulation. Alanine deprivation leads to metabolic and functional impairments. Mechanistically, this vulnerability reflects the low expression of alanine aminotransferase, the enzyme required for interconverting pyruvate and alanine, whereas activated T\&nbsp;cells instead induce alanine transporters. Stable isotope tracing reveals that alanine is not catabolized but instead supports protein synthesis. Thus, T\&nbsp;cells depend on exogenous alanine for protein synthesis and normal activation.},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2019.08.034},
	author = {Ron-Harel, Noga and Ghergurovich, Jonathan M and Notarangelo, Giulia and LaFleur, Martin W and Tsubosaka, Yoshiki and Sharpe, Arlene H and Rabinowitz, Joshua D and Haigis, Marcia C}
}
@article {1453703,
	title = {A Multi-center Study on the Reproducibility of Drug-Response Assays in Mammalian Cell Lines},
	journal = {Cell Syst},
	volume = {9},
	number = {1},
	year = {2019},
	month = {2019 Jul 24},
	pages = {35-48.e5},
	abstract = {Evidence that some high-impact biomedical results cannot be repeated has stimulated interest in practices that generate findable, accessible, interoperable, and reusable (FAIR) data. Multiple papers have identified specific examples of irreproducibility, but practical ways to make data more reproducible have not been widely studied. Here, five research centers in the NIH LINCS Program Consortium investigate the reproducibility of a prototypical perturbational assay: quantifying the responsiveness of cultured cells to anti-cancer drugs. Such assays are important for drug development, studying cellular networks, and patient stratification. While many experimental and computational factors impact intra- and inter-center reproducibility, the factors most difficult to identify and control are those with a strong dependency on biological context. These factors often vary in magnitude with the drug being analyzed and with growth conditions. We provide ways to identify such context-sensitive factors, thereby improving both the theory and practice of reproducible cell-based assays.},
	issn = {2405-4720},
	doi = {10.1016/j.cels.2019.06.005},
	author = {Niepel, Mario and Hafner, Marc and Mills, Caitlin E and Subramanian, Kartik and Williams, Elizabeth H and Chung, Mirra and Gaudio, Benjamin and Barrette, Anne Marie and Stern, Alan D and Hu, Bin and Korkola, James E and LINCS Consortium and Gray, Joe W and Birtwistle, Marc R and Heiser, Laura M and Sorger, Peter K}
}
@article {1453701,
	title = {Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity},
	journal = {Cell Chem Biol},
	year = {2019},
	month = {2019 Jun 06},
	abstract = {The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.},
	issn = {2451-9448},
	doi = {10.1016/j.chembiol.2019.05.005},
	author = {Hafner, Marc and Mills, Caitlin E and Subramanian, Kartik and Chen, Chen and Chung, Mirra and Boswell, Sarah A and Everley, Robert A and Liu, Changchang and Walmsley, Charlotte S and Juric, Dejan and Sorger, Peter K}
}
@article {1453702,
	title = {Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway},
	journal = {Science},
	volume = {364},
	number = {6441},
	year = {2019},
	month = {2019 05 17},
	abstract = {Activation of tumor suppressors for the treatment of human cancer has been a long sought, yet elusive, strategy. PTEN is a critical tumor suppressive phosphatase that is active in its dimer configuration at the plasma membrane. Polyubiquitination by the ubiquitin E3 ligase WWP1 (WW domain-containing ubiquitin E3 ligase 1) suppressed the dimerization, membrane recruitment, and function of PTEN. Either genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation and unleashed tumor suppressive activity. appears to be a direct MYC (MYC proto-oncogene) target gene and was critical for MYC-driven tumorigenesis. We identified indole-3-carbinol, a compound found in cruciferous vegetables, as a natural and potent WWP1 inhibitor. Thus, our findings unravel a potential therapeutic strategy for cancer prevention and treatment through PTEN reactivation.},
	issn = {1095-9203},
	doi = {10.1126/science.aau0159},
	author = {Yu-Ru Lee and Chen, Ming and Lee, Jonathan D and Zhang, Jinfang and Lin, Shu-Yu and Tian-Min Fu and Chen, Hao and Ishikawa, Tomoki and Chiang, Shang-Yin and Katon, Jesse and Zhang, Yang and Shulga, Yulia V and Bester, Assaf C and Fung, Jacqueline and Emanuele Monteleone and Wan, Lixin and Shen, Chen and Hsu, Chih-Hung and Papa, Antonella and Clohessy, John G and Teruya-Feldstein, Julie and Jain, Suresh and Wu, Hao and Matesic, Lydia and Chen, Ruey-Hwa and Wei, Wenyi and Pandolfi, Pier Paolo}
}
@article {1453705,
	title = {Subclonal cooperation drives metastasis by modulating local and systemic immune microenvironments},
	journal = {Nat Cell Biol},
	volume = {21},
	number = {7},
	year = {2019},
	month = {2019 Jul},
	pages = {879-888},
	abstract = {Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote metastatic progression and generate polyclonal metastases composed of driver and neutral subclones. Expression profiling of the epithelial and stromal compartments of monoclonal and polyclonal primary and metastatic lesions revealed that this cooperation is indirect, mediated through the local and systemic microenvironments. We identified neutrophils as a leukocyte population stimulated by the IL11-expressing minor subclone and showed that the depletion of neutrophils prevents metastatic outgrowth. Single-cell RNA-seq of CD45 cell populations from primary tumours, blood and lungs demonstrated that IL11 acts on bone-marrow-derived mesenchymal stromal cells, which induce pro-tumorigenic and pro-metastatic neutrophils. Our results indicate key roles for non-cell-autonomous drivers and minor subclones in metastasis.},
	issn = {1476-4679},
	doi = {10.1038/s41556-019-0346-x},
	author = {Janiszewska, Michalina and Tabassum, Doris P and Casta{\~n}o, Zafira and Cristea, Simona and Yamamoto, Kimiyo N and Kingston, Natalie L and Murphy, Katherine C and Shu, Shaokun and Harper, Nicholas W and Del Alcazar, Carlos Gil and Ale{\v c}kovi{\'c}, Ma{\v s}a and Ekram, Muhammad B and Cohen, Ofir and Kwak, Minsuk and Qin, Yuanbo and Laszewski, Tyler and Luoma, Adrienne and Marusyk, Andriy and Wucherpfennig, Kai W and Wagle, Nikhil and Fan, Rong and Michor, Franziska and McAllister, Sandra S and Polyak, Kornelia}
}
@article {1453704,
	title = {TAM Kinases Promote Necroptosis by Regulating Oligomerization of MLKL},
	journal = {Mol Cell},
	year = {2019},
	month = {2019 Jun 11},
	abstract = {Necroptosis, a cell death pathway mediated by the RIPK1-RIPK3-MLKL signaling cascade downstream of tumor necrosis factor α (TNF-α), has been implicated in many inflammatory diseases. Members of\&nbsp;the TAM (Tyro3, Axl, and Mer) family of receptor tyrosine kinases are known for their anti-apoptotic, oncogenic, and anti-inflammatory roles. Here, we identify an unexpected role of TAM kinases as promoters of necroptosis, a pro-inflammatory necrotic cell death. Pharmacologic or genetic targeting of TAM kinases results in a potent inhibition of necroptotic death in various cellular models. We identify phosphorylation of MLKL Tyr376 as a direct point of\&nbsp;input from TAM kinases into the necroptosis signaling. The oligomerization of MLKL, but not its membranal translocation or phosphorylation by RIPK3, is controlled by TAM kinases. Importantly, both knockout and inhibition of TAM kinases protect mice from systemic inflammatory response syndrome. In conclusion, this study discovers that immunosuppressant\&nbsp;TAM kinases are promoters of\&nbsp;pro-inflammatory necroptosis, shedding light on the\&nbsp;biological complexity of the regulation of inflammation.},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2019.05.022},
	author = {Ayaz Najafov and Mookhtiar, Adnan K and Luu, Hoang Son and Alban Ordureau and Pan, Heling and Amin, Palak P and Li, Ying and Lu, Qingxian and Yuan, Junying}
}
@article {1438158,
	title = {A CRISPR-Cas9 delivery system for in vivo screening of genes in the immune system},
	journal = {Nat Commun},
	volume = {10},
	number = {1},
	year = {2019},
	month = {2019 04 10},
	pages = {1668},
	abstract = {Therapies that target the function of immune cells have significant clinical efficacy in diseases such as cancer and autoimmunity. Although functional genomics has accelerated therapeutic target discovery in cancer, its use in primary immune cells is limited because vector delivery is inefficient and can perturb cell states. Here we describe CHIME: CHimeric IMmune Editing, a CRISPR-Cas9 bone marrow delivery system to rapidly evaluate gene function in innate and adaptive immune cells in vivo without ex vivo manipulation of these mature lineages. This approach enables efficient deletion of genes of interest in major immune lineages without altering their development or function. We use this approach to perform an in vivo pooled genetic screen and identify Ptpn2 as a negative regulator of CD8 T cell-mediated responses to LCMV Clone 13 viral infection. These findings indicate that this genetic platform can enable rapid target discovery through pooled screening in immune cells in vivo.},
	keywords = {Adaptive Immunity, Animals, Bone Marrow Transplantation, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Cell Lineage, Cercopithecus aethiops, CRISPR-Cas Systems, Disease Models, Animal, Feasibility Studies, Female, Gene Transfer Techniques, Genetic Testing, Genetic Vectors, Genomics, HEK293 Cells, Humans, Immunity, Innate, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Protein Tyrosine Phosphatase, Non-Receptor Type 2, RNA, Guide, Transplantation Chimera, Vero Cells},
	issn = {2041-1723},
	doi = {10.1038/s41467-019-09656-2},
	author = {LaFleur, Martin W and Nguyen, Thao H and Coxe, Matthew A and Yates, Kathleen B and Trombley, Justin D and Weiss, Sarah A and Brown, Flavian D and Gillis, Jacob E and Coxe, Daniel J and Doench, John G and Haining, W Nicholas and Sharpe, Arlene H}
}
@article {1438157,
	title = {LLGL2 rescues nutrient stress by promoting leucine uptake in ER breast cancer},
	journal = {Nature},
	volume = {569},
	number = {7755},
	year = {2019},
	month = {2019 May},
	pages = {275-279},
	abstract = {Drosophila Lgl and its mammalian homologues, LLGL1 and LLGL2, are scaffolding proteins that regulate the establishment of apical-basal polarity in epithelial cells. Whereas Lgl functions as a tumour suppressor in Drosophila, the roles of mammalian LLGL1 and LLGL2 in cancer are unclear. The majority (about 75\%) of breast cancers express oestrogen receptors (ERs), and patients with these tumours receive endocrine treatment. However, the development of resistance to endocrine therapy and metastatic progression are leading causes of death for patients with ER disease. Here we report that, unlike LLGL1, LLGL2 is overexpressed in ER breast cancer and promotes cell proliferation under nutrient stress. LLGL2 regulates cell surface levels of a leucine transporter, SLC7A5, by forming a trimeric complex with SLC7A5 and a regulator of membrane fusion, YKT6, to promote leucine uptake and cell proliferation. The oestrogen receptor targets LLGL2 expression. Resistance to endocrine treatment in breast cancer cells was associated with SLC7A5- and LLGL2-dependent adaption to nutrient stress. SLC7A5 was necessary and sufficient to confer resistance to tamoxifen treatment, identifying SLC7A5 as a potential therapeutic target for overcoming resistance to endocrine treatments in breast cancer. Thus, LLGL2 functions as a promoter of tumour growth and not as a tumour suppressor in ER breast cancer. Beyond breast cancer, adaptation to nutrient stress is critically important, and our findings identify an unexpected role for LLGL2 in this process.},
	issn = {1476-4687},
	doi = {10.1038/s41586-019-1126-2},
	author = {Saito, Yasuhiro and Li, Lewyn and Coyaud, Etienne and Luna, Augustin and Sander, Chris and Raught, Brian and Asara, John M and Brown, Myles and Muthuswamy, Senthil K}
}
@article {1427501,
	title = {Genetic Screens Reveal FEN1 and APEX2 as BRCA2 Synthetic Lethal Targets},
	journal = {Mol Cell},
	volume = {73},
	number = {5},
	year = {2019},
	month = {2019 Mar 07},
	pages = {885-899.e6},
	abstract = {BRCA1 or BRCA2 inactivation drives breast and ovarian cancer but also creates vulnerability to poly(ADP-ribose) polymerase (PARP) inhibitors. To search for additional targets whose inhibition is synthetically lethal in BRCA2-deficient backgrounds, we screened two pairs of BRCA2 isogenic cell lines with DNA-repair-focused small hairpin RNA (shRNA) and CRISPR (clustered regularly interspaced short palindromic repeats)-based libraries. We found that BRCA2-deficient cells are selectively dependent on multiple pathways including base excision repair, ATR signaling, and splicing. We identified APEX2 and FEN1 as synthetic lethal genes with both BRCA1 and BRCA2 loss of function. BRCA2-deficient cells require the apurinic endonuclease activity and the PCNA-binding domain of Ape2 (APEX2), but not Ape1 (APEX1). Furthermore, BRCA2-deficient cells require the 5{\textquoteright} flap endonuclease but not the 5{\textquoteright}-3{\textquoteright} exonuclease activity of Fen1, and chemically inhibiting Fen1 selectively targets BRCA-deficient cells. Finally, we developed a microhomology-mediated end-joining (MMEJ) reporter and showed that Fen1 participates in MMEJ, underscoring the importance of MMEJ as a collateral repair pathway in the context of homologous recombination (HR) deficiency.},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2018.12.008},
	author = {Mengwasser, Kristen E and Adeyemi, Richard O and Leng, Yumei and Choi, Mei Yuk and Clairmont, Connor and D{\textquoteright}Andrea, Alan D and Elledge, Stephen J}
}
@article {1427504,
	title = {Human nuclear RNAi-defective 2 (NRDE2) is an essential RNA splicing factor},
	journal = {RNA},
	volume = {25},
	number = {3},
	year = {2019},
	month = {2019 03},
	pages = {352-363},
	abstract = {The accurate inheritance of genetic material is a basic necessity in all domains of life and an unexpectedly large number of RNA processing factors are required for mitotic progression and genome stability. NRDE2 (nuclear RNAi defective-2) is an evolutionarily conserved protein originally discovered for its role in nuclear RNA interference (RNAi) and heritable gene silencing in (). The function of the human gene remains poorly understood. Here we show that human NRDE2 is an essential protein required for suppressing intron retention in a subset of pre-mRNAs containing short, GC-rich introns with relatively weak 5{\textquoteright} and 3{\textquoteright} splice sites. NRDE2 preferentially interacts with components of the U5 small nuclear ribonucleoprotein (snRNP), the exon junction complex, and the RNA exosome. Interestingly, depleted cells exhibit greatly increased levels of genomic instability and DNA damage, as well as defects in centrosome maturation and mitotic progression. We identify the essential centriolar satellite protein, CEP131, as a direct NRDE2-regulated target. NRDE2 specifically binds to and promotes the efficient splicing of pre-mRNA, and depleting dramatically reduces CEP131 protein expression, contributing to impaired recruitment of critical centrosomal proteins (e.g., γ-tubulin and Aurora Kinase A) to the spindle poles during mitosis. Our work establishes a conserved role for human in RNA splicing, characterizes the severe genomic instability phenotypes observed upon loss of , and highlights the direct regulation of splicing as one of multiple mechanisms through which such phenotypes might be explained.},
	issn = {1469-9001},
	doi = {10.1261/rna.069773.118},
	author = {Jiao, Alan L and Perales, Roberto and Umbreit, Neil T and Haswell, Jeffrey R and Piper, Mary E and Adams, Brian D and Pellman, David and Kennedy, Scott and Slack, Frank J}
}
@article {1427502,
	title = {Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment},
	journal = {Cancer Discov},
	volume = {9},
	number = {2},
	year = {2019},
	month = {2019 Feb},
	pages = {176-198},
	abstract = {: Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specific molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profiling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratification of patients, guide treatment decisions and surveillance, and help identify new targets for drug development. SIGNIFICANCE: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identification of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-18-1177},
	author = {Garrido-Castro, Ana C and Lin, Nancy U and Polyak, Kornelia}
}
@article {1427498,
	title = {Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial},
	journal = {Lancet Oncol},
	year = {2019},
	month = {2019 Mar 14},
	abstract = {BACKGROUND: Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. METHODS: In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. FINDINGS: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16\%] of 32 patients), nausea (three [9\%]), and increased alanine aminotransferase concentrations (three [9\%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36\%) achieved a partial response and 14 (50\%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. INTERPRETATION: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. FUNDING: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.},
	issn = {1474-5488},
	doi = {10.1016/S1470-2045(18)30905-7},
	author = {Konstantinopoulos, Panagiotis A and Barry, William T and Birrer, Michael and Westin, Shannon N and Cadoo, Karen A and Shapiro, Geoffrey I and Mayer, Erica L and O{\textquoteright}Cearbhaill, Roisin E and Coleman, Robert L and Kochupurakkal, Bose and Whalen, Christin and Curtis, Jennifer and Farooq, Sarah and Luo, Weixiu and Eismann, Julia and Buss, Mary K and Aghajanian, Carol and Mills, Gordon B and Palakurthi, Sangeetha and Kirschmeier, Paul and Liu, Joyce and Cantley, Lewis C and Kaufmann, Scott H and Swisher, Elizabeth M and D{\textquoteright}Andrea, Alan D and Winer, Eric and Wulf, Gerburg M and Matulonis, Ursula A}
}
@article {1427499,
	title = {Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity},
	journal = {Cell},
	volume = {176},
	number = {6},
	year = {2019},
	month = {2019 Mar 07},
	pages = {1265-1281.e24},
	abstract = {Acute myeloid leukemia (AML) is a heterogeneous disease that resides within a complex microenvironment, complicating efforts to understand how different cell types contribute to disease progression. We combined single-cell RNA sequencing and genotyping to profile 38,410 cells from 40 bone marrow aspirates, including 16 AML patients and five healthy donors. We then applied a machine learning classifier to distinguish a spectrum of malignant cell types whose abundances varied between patients and between subclones in the same tumor. Cell type compositions correlated with prototypic genetic lesions, including an association of FLT3-ITD with abundant progenitor-like cells. Primitive AML cells exhibited dysregulated transcriptional programs with co-expression of stemness and myeloid priming genes and had prognostic significance. Differentiated monocyte-like AML cells expressed diverse immunomodulatory genes and suppressed T\&nbsp;cell activity in\&nbsp;vitro. In conclusion, we provide single-cell technologies and an atlas of AML cell states, regulators, and markers with implications for precision medicine and immune therapies. VIDEO ABSTRACT.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2019.01.031},
	author = {van Galen, Peter and Hovestadt, Volker and Wadsworth Ii, Marc H and Hughes, Travis K and Griffin, Gabriel K and Battaglia, Sofia and Verga, Julia A and Stephansky, Jason and Pastika, Timothy J and Lombardi Story, Jennifer and Pinkus, Geraldine S and Pozdnyakova, Olga and Galinsky, Ilene and Stone, Richard M and Graubert, Timothy A and Shalek, Alex K and Aster, Jon C and Lane, Andrew A and Bernstein, Bradley E}
}
@article {1427505,
	title = {Defective respiration and one-carbon metabolism contribute to impaired na{\"\i}ve T cell activation in aged mice},
	journal = {Proc Natl Acad Sci U S A},
	volume = {115},
	number = {52},
	year = {2018},
	month = {2018 12 26},
	pages = {13347-13352},
	abstract = {T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged na{\"\i}ve T cell activation. We observed a decrease in the number and activation of na{\"\i}ve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged na{\"\i}ve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.},
	issn = {1091-6490},
	doi = {10.1073/pnas.1804149115},
	author = {Ron-Harel, Noga and Notarangelo, Giulia and Ghergurovich, Jonathan M and Paulo, Joao A and Sage, Peter T and Santos, Daniel and Satterstrom, F Kyle and Gygi, Steven P and Rabinowitz, Joshua D and Sharpe, Arlene H and Haigis, Marcia C}
}
@article {1427503,
	title = {Hidden heterogeneity and circadian-controlled cell fate inferred from single cell lineages},
	journal = {Nat Commun},
	volume = {9},
	number = {1},
	year = {2018},
	month = {2018 12 18},
	pages = {5372},
	abstract = {The origin of lineage correlations among single cells and the extent of heterogeneity in their intermitotic times (IMT) and apoptosis times (AT) remain incompletely understood. Here we developed single cell lineage-tracking experiments and computational algorithms to uncover correlations and heterogeneity in the IMT and AT of a colon cancer cell line before and during cisplatin treatment. These correlations could not be explained using simple protein production/degradation models. Sister cell fates were similar regardless of whether they divided before or after cisplatin administration and did not arise from proximity-related factors, suggesting fate determination early in a cell{\textquoteright}s lifetime. Based on these findings, we developed a theoretical model explaining how the observed correlation structure can arise from oscillatory mechanisms underlying cell fate control. Our model recapitulated the data only with very specific oscillation periods that fit measured circadian rhythms, thereby suggesting an important role of the circadian clock in controlling cellular fates.},
	keywords = {Algorithms, Apoptosis, Cell Differentiation, Cell Lineage, Circadian Clocks, Circadian Rhythm, HCT116 Cells, Humans, Image Processing, Computer-Assisted, Intravital Microscopy, Models, Biological, Single-Cell Analysis, Software},
	issn = {2041-1723},
	doi = {10.1038/s41467-018-07788-5},
	author = {Chakrabarti, Shaon and Paek, Andrew L and Reyes, Jose and Lasick, Kathleen A and Lahav, Galit and Michor, Franziska}
}
@article {1427500,
	title = {KDM5 Histone Demethylase Activity Links Cellular Transcriptomic Heterogeneity to Therapeutic Resistance},
	journal = {Cancer Cell},
	volume = {34},
	number = {6},
	year = {2018},
	month = {2019 Feb 11},
	pages = {939-953},
	abstract = {Members of the KDM5 histone H3 lysine 4 demethylase family are associated with therapeutic resistance, including endocrine resistance in breast cancer, but the underlying mechanism is poorly defined. Here we\&nbsp;show that genetic deletion of KDM5A/B or inhibition of KDM5 activity increases sensitivity to anti-estrogens by modulating estrogen receptor (ER) signaling and by decreasing cellular transcriptomic heterogeneity. Higher KDM5B expression levels are associated with higher transcriptomic heterogeneity and poor prognosis in ER+\&nbsp;breast tumors. Single-cell RNA sequencing, cellular barcoding, and mathematical modeling demonstrate that endocrine resistance is due to selection for pre-existing genetically distinct cells, while KDM5 inhibitor resistance is acquired. Our findings highlight the importance of cellular phenotypic heterogeneity in therapeutic resistance and identify KDM5A/B as key regulators of this process.},
	issn = {1878-3686},
	doi = {10.1016/j.ccell.2019.01.012},
	author = {Hinohara, Kunihiko and Wu, Hua-Jun and Wu, Hua-Jun and McDonald, Thomas O and Igarashi, Kyomi J and Yamamoto, Kimiyo N and Madsen, Thomas and Fassl, Anne and Egri, Shawn B and Papanastasiou, Malvina and Ding, Lina and Peluffo, Guillermo and Cohen, Ofir and Kales, Stephen C and Lal-Nag, Madhu and Rai, Ganesha and Maloney, David J and Jadhav, Ajit and Simeonov, Anton and Wagle, Nikhil and Brown, Myles and Meissner, Alexander and Sicinski, Piotr and Jaffe, Jacob D and Jeselsohn, Rinath and Gimelbrant, Alexander A and Michor, Franziska and Polyak, Kornelia}
}
@article {1354668,
	title = {BRAF and AXL oncogenes drive RIPK3 expression loss in cancer},
	journal = {PLoS Biol},
	volume = {16},
	number = {8},
	year = {2018},
	month = {2018 Aug},
	pages = {e2005756},
	abstract = {Necroptosis is a lytic programmed cell death mediated by the RIPK1-RIPK3-MLKL pathway. The loss of Receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression and necroptotic potential have been previously reported in several cancer cell lines; however, the extent of this loss across cancer types, as well as its mutational drivers, were unknown. Here, we show that RIPK3 expression loss occurs progressively during tumor growth both in patient tumor biopsies and tumor xenograft models. Using a cell-based necroptosis sensitivity screen of 941 cancer cell lines, we find that escape from necroptosis is prevalent across cancer types, with an incidence rate of 83\%. Genome-wide bioinformatics analysis of this differential necroptosis sensitivity data in the context of differential gene expression and mutation data across the cell lines identified various factors that correlate with resistance to necroptosis and loss of RIPK3 expression, including oncogenes BRAF and AXL. Inhibition of these oncogenes can rescue the RIPK3 expression loss and regain of necroptosis sensitivity. This genome-wide analysis also identifies that the loss of RIPK3 expression is the primary factor correlating with escape from necroptosis. Thus, we conclude that necroptosis resistance of cancer cells is common and is oncogene driven, suggesting that escape from necroptosis could be a potential hallmark of cancer, similar to escape from apoptosis.},
	issn = {1545-7885},
	doi = {10.1371/journal.pbio.2005756},
	author = {Ayaz Najafov and Zervantonakis, Ioannis K and Mookhtiar, Adnan K and Greninger, Patricia and March, Ryan J and Egan, Regina K and Luu, Hoang Son and Stover, Daniel G and Matulonis, Ursula A and Benes, Cyril H and Yuan, Junying}
}
@article {1354665,
	title = {A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade},
	journal = {Cell},
	volume = {175},
	number = {4},
	year = {2018},
	month = {2018 Nov 01},
	pages = {984-997.e24},
	abstract = {Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the\&nbsp;molecular underpinnings of such resistance remain\&nbsp;elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T\&nbsp;cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in\&nbsp;vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2018.09.006},
	author = {Jerby-Arnon, Livnat and Shah, Parin and Cuoco, Michael S and Rodman, Christopher and Su, Mei-Ju and Melms, Johannes C and Leeson, Rachel and Kanodia, Abhay and Mei, Shaolin and Lin, Jia-Ren and Wang, Shu and Rabasha, Bokang and Liu, David and Zhang, Gao and Margolais, Claire and Ashenberg, Orr and Ott, Patrick A and Buchbinder, Elizabeth I and Haq, Rizwan and Hodi, F Stephen and Boland, Genevieve M and Sullivan, Ryan J and Frederick, Dennie T and Miao, Benchun and Moll, Tabea and Flaherty, Keith T and Herlyn, Meenhard and Jenkins, Russell W and Thummalapalli, Rohit and Kowalczyk, Monika S and Ca{\~n}adas, Israel and Schilling, Bastian and Cartwright, Adam N R and Luoma, Adrienne M and Malu, Shruti and Hwu, Patrick and Bernatchez, Chantale and Forget, Marie-Andr{\'e}e and Barbie, David A and Shalek, Alex K and Itay Tirosh and Sorger, Peter K and Wucherpfennig, Kai and Van Allen, Eliezer M and Schadendorf, Dirk and Johnson, Bruce E and Rotem, Asaf and Rozenblatt-Rosen, Orit and Garraway, Levi A and Yoon, Charles H and Izar, Benjamin and Regev, Aviv}
}
@article {1354666,
	title = {Currently available bulk sequencing data do not necessarily support a model of neutral tumor evolution},
	journal = {Nat Genet},
	year = {2018},
	month = {2018 Oct 29},
	issn = {1546-1718},
	doi = {10.1038/s41588-018-0217-6},
	author = {McDonald, Thomas O and Chakrabarti, Shaon and Michor, Franziska}
}
@article {1354670,
	title = {Dissecting the mammary gland one cell at a time},
	journal = {Nat Commun},
	volume = {9},
	number = {1},
	year = {2018},
	month = {2018 Jun 26},
	pages = {2473},
	abstract = {Dissecting cellular differentiation hierarchies in the mammary gland is a prerequisite for understanding both normal development and malignant transformation during tumorigenesis and tumor cell-of-origin. To achieve these goals, several recent papers utilized single cell RNA-seq and lineage tracing to improve our understanding of the composition of the mammary epithelium at different developmental stages.},
	issn = {2041-1723},
	doi = {10.1038/s41467-018-04905-2},
	author = {Cristea, Simona and Polyak, Kornelia}
}
@article {1354672,
	title = {Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges},
	journal = {Nat Rev Clin Oncol},
	volume = {15},
	number = {5},
	year = {2018},
	month = {2018 May},
	pages = {325-340},
	abstract = {Immunotherapy has emerged as a major therapeutic modality in oncology. Currently, however, the majority of patients with cancer do not derive benefit from these treatments. Vascular abnormalities are a hallmark of most solid tumours and facilitate immune evasion. These abnormalities stem from elevated levels of proangiogenic factors, such as VEGF and angiopoietin 2 (ANG2); judicious use of drugs targeting these molecules can improve therapeutic responsiveness, partially owing to normalization of the abnormal tumour vasculature that can, in turn, increase the infiltration of immune effector cells into tumours and convert the intrinsically immunosuppressive tumour microenvironment (TME) to an immunosupportive one. Immunotherapy relies on the accumulation and activity of immune effector cells within the TME, and immune responses and vascular normalization seem to be reciprocally regulated. Thus, combining antiangiogenic therapies and immunotherapies might increase the effectiveness of immunotherapy and diminish the risk of immune-related adverse effects. In this Perspective, we outline the roles of VEGF and ANG2 in tumour immune evasion and progression, and discuss the evidence indicating that antiangiogenic agents can normalize the TME. We also suggest ways that antiangiogenic agents can be combined with immune-checkpoint inhibitors to potentially improve patient outcomes, and highlight avenues of future research.},
	issn = {1759-4782},
	doi = {10.1038/nrclinonc.2018.29},
	author = {Fukumura, Dai and Kloepper, Jonas and Amoozgar, Zohreh and Duda, Dan G and Jain, Rakesh K}
}
@article {1354669,
	title = {Highly multiplexed immunofluorescence imaging of human tissues and tumors using t-CyCIF and conventional optical microscopes},
	journal = {Elife},
	volume = {7},
	year = {2018},
	month = {2018 Jul 11},
	abstract = {The architecture of normal and diseased tissues strongly influences the development and progression of disease as well as responsiveness and resistance to therapy. We describe a tissue-based cyclic immunofluorescence (t-CyCIF) method for highly multiplexed immuno-fluorescence imaging of formalin-fixed, paraffin-embedded (FFPE) specimens mounted on glass slides, the most widely used specimens for histopathological diagnosis of cancer and other diseases. t-CyCIF generates up to 60-plex images using an iterative process (a cycle) in which conventional low-plex fluorescence images are repeatedly collected from the same sample and then assembled into a high-dimensional representation. t-CyCIF requires no specialized instruments or reagents and is compatible with super-resolution imaging; we demonstrate its application to quantifying signal transduction cascades, tumor antigens and immune markers in diverse tissues and tumors. The simplicity and adaptability of t-CyCIF makes it an effective method for pre-clinical and clinical research and a natural complement to single-cell genomics.},
	issn = {2050-084X},
	doi = {10.7554/eLife.31657},
	author = {Lin, Jia-Ren and Izar, Benjamin and Wang, Shu and Yapp, Clarence and Mei, Shaolin and Shah, Parin M and Santagata, Sandro and Sorger, Peter K}
}
@article {1354671,
	title = {Modulating Cell Fate as a Therapeutic Strategy},
	journal = {Cell Stem Cell},
	volume = {23},
	number = {3},
	year = {2018},
	month = {2018 Sep 06},
	pages = {329-341},
	abstract = {In injured tissues, regeneration is often associated with cell fate plasticity, in that cells deviate from their normal lineage paths. It is becoming increasingly clear that this plasticity often creates alternative strategies to restore damaged or lost cells. Alternatively, cell fate plasticity is also part and parcel of pathologic tissue transformations that accompany disease. In this Perspective, we summarize a few illustrative examples of physiologic and aberrant cellular plasticity. Then, we speculate on how one could enhance endogenous plasticity to promote regeneration and reverse pathologic plasticity, perhaps inspiring interest in a new class of therapies targeting cell fate modulation.},
	issn = {1875-9777},
	doi = {10.1016/j.stem.2018.05.009},
	author = {Lin, Brian and Srikanth, Priya and Castle, Alison C and Nigwekar, Sagar and Malhotra, Rajeev and Galloway, Jenna L and Sykes, David B and Rajagopal, Jayaraj}
}
@article {1354673,
	title = {Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma},
	journal = {Neuro Oncol},
	volume = {20},
	number = {8},
	year = {2018},
	month = {2018 Jul 05},
	pages = {1101-1112},
	abstract = {Background: Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) subtypes. Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in ACP and PCP. Methods: We mapped and quantified PD-L1 and PD-1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1. Results: All ACP (15 {\textpm} 14\% of cells, n = 23, average {\textpm} SD) and PCP (35 {\textpm} 22\% of cells, n = 18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst lining. In PCP, PD-L1 was highly expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T cells. Conclusions: ACP exhibit PD-L1 expression in the tumor cyst lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy.},
	issn = {1523-5866},
	doi = {10.1093/neuonc/noy035},
	author = {Coy, Shannon and Rashid, Rumana and Lin, Jia-Ren and Du, Ziming and Donson, Andrew M and Hankinson, Todd C and Foreman, Nicholas K and Manley, Peter E and Kieran, Mark W and Reardon, David A and Sorger, Peter K and Santagata, Sandro}
}
@article {1354667,
	title = {Unravelling subclonal heterogeneity and aggressive disease states in TNBC through single-cell RNA-seq},
	journal = {Nat Commun},
	volume = {9},
	number = {1},
	year = {2018},
	month = {2018 Sep 04},
	pages = {3588},
	abstract = {Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conducted single-cell RNA-sequencing (scRNA-seq) of \&gt;1500 cells from six primary TNBC. Here, we show that intercellular heterogeneity of gene expression programs within each tumor is variable and largely correlates with clonality of inferred genomic copy number changes, suggesting that genotype drives the gene expression phenotype of individual subpopulations. Clustering of gene expression profiles identified distinct subgroups of malignant cells shared by multiple tumors, including a single subpopulation associated with multiple signatures of treatment resistance and metastasis, and characterized functionally by activation of glycosphingolipid metabolism and associated innate immunity pathways. A novel signature defining this subpopulation predicts long-term outcomes for TNBC patients in a large cohort. Collectively, this analysis reveals the functional heterogeneity and its association with genomic evolution in TNBC, and uncovers unanticipated biological principles dictating poor outcomes in this disease.},
	issn = {2041-1723},
	doi = {10.1038/s41467-018-06052-0},
	author = {Karaayvaz, Mihriban and Cristea, Simona and Gillespie, Shawn M and Patel, Anoop P and Mylvaganam, Ravindra and Luo, Christina C and Specht, Michelle C and Bernstein, Bradley E and Michor, Franziska and Ellisen, Leif W}
}
@article {1324398,
	title = {Modeling chemotherapy-induced stress to identify rational combination therapies in the DNA damage response pathway},
	journal = {Sci Signal},
	volume = {11},
	number = {540},
	year = {2018},
	month = {2018 Jul 24},
	abstract = {Cells respond to DNA damage by activating complex signaling networks that decide cell fate, promoting not only DNA damage repair and survival but also cell death. We have developed a multiscale computational model that quantitatively links chemotherapy-induced DNA damage response signaling to cell fate. The computational model was trained and calibrated on extensive data from U2OS osteosarcoma cells, including the cell cycle distribution of the initial cell population, signaling data measured by Western blotting, and cell fate data in response to chemotherapy treatment measured by time-lapse microscopy. The resulting mechanistic model predicted the cellular responses to chemotherapy alone and in combination with targeted inhibitors of the DNA damage response pathway, which we confirmed experimentally. Computational models such as the one presented here can be used to understand the molecular basis that defines the complex interplay between cell survival and cell death and to rationally identify chemotherapy-potentiating drug combinations.},
	issn = {1937-9145},
	doi = {10.1126/scisignal.aat0229},
	author = {Alkan, Ozan and Schoeberl, Birgit and Shah, Millie and Koshkaryev, Alexander and Heinemann, Tim and Drummond, Daryl C and Yaffe, Michael B and Raue, Andreas}
}
@article {1319515,
	title = {Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas},
	journal = {Leukemia},
	year = {2018},
	month = {2018 Jun 26},
	abstract = {Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein-Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.},
	issn = {1476-5551},
	doi = {10.1038/s41375-018-0178-x},
	author = {Anastasiadou, Eleni and Stroopinsky, Dina and Alimperti, Stella and Jiao, Alan L and Pyzer, Athalia R and Cippitelli, Claudia and Pepe, Giuseppina and Severa, Martina and Rosenblatt, Jacalyn and Etna, Marilena P and Rieger, Simone and Kempkes, Bettina and Coccia, Eliana M and Sui, Shannan J Ho and Chen, Christopher S and Uccini, Stefania and Avigan, David and Faggioni, Alberto and Trivedi, Pankaj and Slack, Frank J}
}
@article {1313640,
	title = {Cancer Cells Co-opt the Neuronal Redox-Sensing Channel TRPA1 to Promote Oxidative-Stress Tolerance},
	journal = {Cancer Cell},
	year = {2018},
	abstract = {Cancer cell survival is dependent on oxidative-stress defenses against reactive oxygen species (ROS) that accumulate during tumorigenesis. Here, we show a non-canonical oxidative-stress defense mechanism through TRPA1, a neuronal redox-sensing Ca2+-influx channel. In TRPA1-enriched breast and lung cancer spheroids, TRPA1 is critical for survival of inner cells that exhibit ROS accumulation. Moreover, TRPA1 promotes resistance to ROS-producing chemotherapies, and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity. TRPA1 does not affect redox status but upregulates Ca2+-dependent anti-apoptotic pathways. NRF2, an oxidant-defense transcription factor, directly controls TRPA1 expression, thus providing an orthogonal mechanism for protection against oxidative stress together with canonical ROS-neutralizing mechanisms. These findings reveal an oxidative-stress defense program involving TRPA1 that could be exploited for targeted cancer therapies.},
	url = {https://www.sciencedirect.com/science/article/pii/S1535610818301831},
	author = {Nobuaki Takahashi and Hsing-Yu Chen and Isaac Harris and Daniel Stover and Laura Selfors and Bronson, Roderick and De Raedt, Thomas and Cichowski, Karen and Yasuo Mori and Mills, Gordon and Joan Brugge}
}
@article {1308851,
	title = {An Integrated Genome-wide CRISPRa Approach to Functionalize lncRNAs in Drug Resistance},
	journal = {Cell},
	volume = {173},
	number = {3},
	year = {2018},
	pages = {649-664},
	abstract = {Resistance to chemotherapy plays a significant role\&nbsp;in cancer mortality. To identify genetic units affecting sensitivity to cytarabine, the mainstay of treatment for acute myeloid leukemia (AML), we\&nbsp;developed a comprehensive and integrated genome-wide platform based on a dual protein-coding and non-coding integrated CRISPRa screening (DICaS). Putative resistance genes were initially identified using pharmacogenetic data from 760 human pan-cancer cell lines. Subsequently, genome scale functional characterization of both coding and long non-coding RNA (lncRNA) genes by CRISPR activation was performed. For lncRNA functional assessment, we developed a CRISPR activation of lncRNA (CaLR) strategy, targeting 14,701 lncRNA genes. Computational and functional analysis identified novel cell-cycle, survival/apoptosis, and cancer signaling genes. Furthermore, transcriptional activation of the GAS6-AS2 lncRNA, identified in our analysis, leads to hyperactivation of the GAS6/TAM pathway, a resistance mechanism in multiple cancers including AML. Thus, DICaS represents a novel and powerful approach to identify integrated coding and non-coding pathways of therapeutic relevance.},
	url = {http://www.cell.com/cell/fulltext/S0092-8674(18)30384-2},
	author = {Assaf C. Bester and Jonathan D. Lee and Chavez, Alejandro and Yu-Ru Lee and Daphna Nachmani and Vora, Suhani and Joshua Victor and Martin Sauvageau and Emanuele Monteleone and Rinn, John L and Paolo Provero and Church, George M and Clohessy, John G and Pier Paolo Pandofi}
}
@article {1303685,
	title = {Skp2-dependent reactivation of AKT drives resistance to PI3K inhibitors},
	journal = {Science Signaling},
	volume = {11},
	number = {521},
	year = {2018},
	abstract = {The PI3K-AKT kinase signaling pathway is frequently deregulated in human cancers, particularly breast cancer, where amplification and somatic mutations of\&nbsp;PIK3CA\&nbsp;occur with high frequency in patients. Numerous small-molecule inhibitors targeting both PI3K and AKT are under clinical evaluation, but dose-limiting toxicities and the emergence of resistance limit therapeutic efficacy. Various resistance mechanisms to PI3K inhibitors have been identified, including de novo mutations, feedback activation of AKT, or cross-talk pathways. We found a previously unknown resistance mechanism to PI3K pathway inhibition that results in AKT rebound activation. In a subset of triple-negative breast cancer cell lines, treatment with a PI3K inhibitor or depletion of\&nbsp;PIK3CA\&nbsp;expression ultimately promoted AKT reactivation in a manner dependent on the E3 ubiquitin ligase Skp2, the kinases IGF-1R (insulin-like growth factor 1 receptor) and PDK-1 (phosphoinositide-dependent kinase-1), and the cell growth and metabolism-regulating complex mTORC2 (mechanistic target of rapamycin complex 2), but was independent of PI3K activity or PIP3\&nbsp;production. Resistance to PI3K inhibitors correlated with the increased abundance of Skp2, ubiquitylation of AKT, cell proliferation in culture, and xenograft tumor growth in mice. These findings reveal a ubiquitin signaling feedback mechanism by which PI3K inhibitor resistance may emerge in aggressive breast cancer cells.},
	author = {Emilie Clement and Inuzuka, Hiroyuki and Naoe Nihira and Wei, Wenyi and Toker, Alex}
}
@article {1299317,
	title = {Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer},
	journal = {Cancer Discov},
	year = {2017},
	month = {2017 Dec 04},
	abstract = {Triple negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole exome sequencing (WES) and RNAseq to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expressions or oncoprotein-containing fusions, respectively, as well as frame-shift mutations of tumor suppressors were identified in approximately 50\% of the tumors evaluated. While the spectrum of sporadic genetic alterations was diverse, the majority had in common the ability to activate the MAPK/PI3K pathways. Importantly, we demonstrated that approved or experimental drugs efficiently induce tumor regression specifically in tumors harboring somatic aberrations of the drug target. Our study suggests that the combination of WES and RNAseq on human TNBC will lead to the identification of actionable therapeutic targets for precision medicine guided TNBC treatment.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-17-0679},
	url = {http://cancerdiscovery.aacrjournals.org/content/early/2017/12/02/2159-8290.CD-17-0679},
	author = {Liu, Hui and Murphy, Charles J and Karreth, Florian A and Emdal, Kristina B and White, Forest M and Elemento, Olivier and Toker, Alex and Wulf, Gerburg M and Cantley, Lewis C}
}
@article {1283306,
	title = {Oncogenic PI3K promotes methionine dependency in breast cancer cells through the cystine-glutamate antiporter xCT},
	journal = {Science Signaling},
	volume = {10},
	number = {510},
	year = {2017},
	abstract = {The precursor homocysteine is metabolized either through the methionine cycle to produce methionine or through the transsulfuration pathway to synthesize cysteine. Alternatively, cysteine can be obtained through uptake of its oxidized form, cystine. Many cancer cells exhibit methionine dependency such that their proliferation is impaired in growth media in which methionine is replaced by homocysteine. We showed that oncogenic PIK3CA and decreased expression of SLC7A11, a gene that encodes a cystine transporter also known as xCT, correlated with increased methionine dependency in breast cancer cells. Oncogenic PIK3CA was sufficient to confer methionine dependency to mammary epithelial cells, partly by decreasing cystine uptake through the transcriptional and posttranslational inhibition of xCT. Manipulation of xCT activity altered the proliferation of breast cancer cells in methionine-deficient, homocysteine-containing media, suggesting that it functionally contributed to methionine dependency. We propose that concurrent with decreased cystine uptake through xCT, PIK3CA mutant cells use homocysteine through the transsulfuration pathway to synthesize cysteine. Consequently, less homocysteine is available to produce methionine, contributing to methionine dependency. These results indicate that oncogenic PIK3CA alters methionine and cysteine utilization, partly by inhibiting xCT to contribute to the methionine dependency phenotype in breast cancer cells.},
	url = {http://stke.sciencemag.org/content/10/510/eaao6604?utm_campaign=toc_signaling_2017-12-19\&et_rid=33942989\&et_cid=1743530},
	author = {Lien, Evan C and Laura Ghisolfi and Renee C Geck and Asara, John M and Toker, Alex}
}
@article {1283281,
	title = {Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy},
	journal = {Cell},
	volume = {171},
	number = {7},
	year = {2017},
	month = {2017 Dec 14},
	pages = {1678-1691.e13},
	abstract = {Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2017.11.009},
	author = {Palmer, Adam C and Sorger, Peter K}
}
@article {1283296,
	title = {Conservation and Divergence of p53 Oscillation Dynamics across Species},
	journal = {Cell Syst},
	volume = {5},
	number = {4},
	year = {2017},
	month = {2017 Oct 25},
	pages = {410-417.e4},
	abstract = {The tumor-suppressing transcription factor p53 is highly conserved at the protein level and plays a key role in the DNA damage response. One important aspect of p53 regulation is its dynamics in response to DNA damage, which include oscillations. Here, we observe that, while the qualitative oscillatory nature of p53 dynamics is conserved across cell lines derived from human, monkey, dog, mouse, and rat, the oscillation period is variable. Specifically, rodent cells exhibit rapid p53 oscillations, whereas dog, monkey, and human cells show slower oscillations. Computational modeling and experiments identify stronger negative feedback between p53 and MDM2 as the driver of faster oscillations in rodents, suggesting that the period of oscillation is a network-level property. In total, our study shows that despite highly conserved signaling, the quantitative features of p53 oscillations can diverge across evolution. We caution that strong amino acid conservation of proteins and transcriptional network similarity do not necessarily imply conservation of time dynamics.},
	issn = {2405-4712},
	doi = {10.1016/j.cels.2017.09.012},
	author = {Stewart-Ornstein, Jacob and Cheng, Ho Wa Jacky and Lahav, Galit}
}
@article {1283286,
	title = {mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors},
	journal = {Cancer Discov},
	volume = {7},
	number = {12},
	year = {2017},
	month = {2017 12},
	pages = {1450-1463},
	abstract = {Although agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here, we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin antioxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating apoptosis signal-regulating kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non-small cell lung cancers. Together, these studies identify a promising therapeutic combination for several currently untreatable malignancies and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.Significance: There are no effective therapies for NF1- or RAS-mutant cancers. We show that combined mTOR/HDAC inhibitors kill these RAS-driven tumors by causing catastrophic oxidative stress. This study identifies a promising therapeutic combination and demonstrates that selective enhancement of oxidative stress may be more broadly exploited for developing cancer therapies. Cancer Discov; 7(12); 1450-63. {\textcopyright}2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-17-0177},
	author = {Malone, Clare F and Emerson, Chloe and Ingraham, Rachel and Barbosa, William and Guerra, Stephanie and Yoon, Haejin and Liu, Lin L and Michor, Franziska and Haigis, Marcia and Macleod, Kay F and Maertens, Oph{\'e}lia and Cichowski, Karen}
}
@article {1283291,
	title = {Non-Euclidean phasor analysis for quantification of oxidative stress in ex vivo human skin exposed to sun filters using fluorescence lifetime imaging microscopy},
	journal = {J Biomed Opt},
	volume = {22},
	number = {12},
	year = {2017},
	month = {2017 Dec},
	pages = {1-10},
	abstract = {Chemical sun filters are commonly used as active ingredients in sunscreens due to their efficient absorption of ultraviolet (UV) radiation. Yet, it is known that these compounds can photochemically react with UV light and generate reactive oxygen species and oxidative stress in vitro, though this has yet to be validated in vivo. One label-free approach to probe oxidative stress is to measure and compare the relative endogenous fluorescence generated by cellular coenzymes nicotinamide adenine dinucleotides and flavin adenine dinucleotides. However, chemical sun filters are fluorescent, with emissive properties that contaminate endogenous fluorescent signals. To accurately distinguish the source of fluorescence in ex vivo skin samples treated with chemical sun filters, fluorescence lifetime imaging microscopy data were processed on a pixel-by-pixel basis using a non-Euclidean separation algorithm based on Mahalanobis distance and validated on simulated data. Applying this method, ex vivo samples exhibited a small oxidative shift when exposed to sun filters alone, though this shift was much smaller than that imparted by UV irradiation. Given the need for investigative tools to further study the clinical impact of chemical sun filters in patients, the reported methodology may be applied to visualize chemical sun filters and measure oxidative stress in patients{\textquoteright} skin.},
	issn = {1560-2281},
	doi = {10.1117/1.JBO.22.12.125004},
	author = {Osseiran, Sam and Roider, Elisabeth M and Wang, Hequn and Suita, Yusuke and Murphy, Michael and Fisher, David E and Evans, Conor L}
}
@article {1283276,
	title = {Orthologous CRISPR-Cas9 enzymes for combinatorial genetic screens},
	journal = {Nat Biotechnol},
	year = {2017},
	month = {2017 Dec 18},
	abstract = {Combinatorial genetic screening using CRISPR-Cas9 is a useful approach to uncover redundant genes and to explore complex gene networks. However, current methods suffer from interference between the single-guide RNAs (sgRNAs) and from limited gene targeting activity. To increase the efficiency of combinatorial screening, we employ orthogonal Cas9 enzymes from Staphylococcus aureus and Streptococcus pyogenes. We used machine learning to establish S. aureus Cas9 sgRNA design rules and paired S. aureus Cas9 with S. pyogenes Cas9 to achieve dual targeting in a high fraction of cells. We also developed a lentiviral vector and cloning strategy to generate high-complexity pooled dual-knockout libraries to identify synthetic lethal and buffering gene pairs across multiple cell types, including MAPK pathway genes and apoptotic genes. Our orthologous approach also enabled a screen combining gene knockouts with transcriptional activation, which revealed genetic interactions with TP53. The "Big Papi" (paired aureus and pyogenes for interactions) approach described here will be widely applicable for the study of combinatorial phenotypes.},
	issn = {1546-1696},
	doi = {10.1038/nbt.4048},
	author = {Najm, Fadi J and Strand, Christine and Donovan, Katherine F and Hegde, Mudra and Sanson, Kendall R and Vaimberg, Emma W and Sullender, Meagan E and Hartenian, Ella and Kalani, Zohra and Fusi, Nicolo and Listgarten, Jennifer and Scott T Younger and Bernstein, Bradley E and Root, David E and Doench, John G}
}
@article {1221716,
	title = {In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target},
	journal = {Nature},
	volume = {547},
	number = {7664},
	year = {2017},
	month = {2017 Jul 27},
	pages = {413-418},
	abstract = {Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-γ signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-κB signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.},
	issn = {1476-4687},
	doi = {10.1038/nature23270},
	author = {Manguso, Robert T and Pope, Hans W and Zimmer, Margaret D and Brown, Flavian D and Yates, Kathleen B and Miller, Brian C and Collins, Natalie B and Bi, Kevin and LaFleur, Martin W and Juneja, Vikram R and Weiss, Sarah A and Lo, Jennifer and Fisher, David E and Miao, Diana and Van Allen, Eliezer and Root, David E and Sharpe, Arlene H and Doench, John G and Haining, W Nicholas}
}
@article {1215961,
	title = {EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation},
	journal = {Nat Cell Biol},
	year = {2017},
	month = {2017 Oct 16},
	abstract = {The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease. Low EZH2 levels reduce H3K27 methylation, prevent MUS81 recruitment at stalled forks and cause fork stabilization. As a consequence, loss of function of the EZH2/MUS81 axis promotes PARPi resistance in BRCA2-deficient cells. Accordingly, low EZH2 or MUS81 expression levels predict chemoresistance and poor outcome in patients with BRCA2-mutated tumours. Moreover, inhibition of Ezh2 in a murine Brca2(-/-) breast tumour model is associated with acquired PARPi resistance. Our findings identify EZH2 as a critical regulator of genomic stability at stalled forks that couples histone modifications to nuclease recruitment. Our data identify EZH2 expression as a biomarker of BRCA2-deficient tumour response to\&nbsp;chemotherapy.},
	issn = {1476-4679},
	doi = {10.1038/ncb3626},
	author = {Rondinelli, Beatrice and Gogola, Ewa and Y{\"u}cel, Hatice and Duarte, Alexandra A and van de Ven, Marieke and van der Sluijs, Roxanne and Konstantinopoulos, Panagiotis A and Jonkers, Jos and Ceccaldi, Rapha{\"e}l and Rottenberg, Sven and D{\textquoteright}Andrea, Alan D}
}
@article {1215966,
	title = {Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass},
	journal = {Science},
	year = {2017},
	month = {2017 Oct 12},
	abstract = {Ammonia is a ubiquitous by-product of cellular metabolism, however the biological consequences of ammonia production are not fully understood, especially in cancer. We find that ammonia is not merely a toxic waste product, but is recycled into central amino acid metabolism to maximize nitrogen utilization. Cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH), and secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment, and was used directly to generate amino acids through GDH activity. These data show that ammonia not only is a secreted waste product, but a fundamental nitrogen source that can support tumor biomass.},
	issn = {1095-9203},
	doi = {10.1126/science.aam9305},
	author = {Spinelli, Jessica B and Yoon, Haejin and Ringel, Alison E and Jeanfavre, Sarah and Clish, Clary B and Haigis, Marcia C}
}
@article {1172336,
	title = {AKT1(low) quiescent cancer cells persist after neoadjuvant chemotherapy in triple negative breast cancer},
	journal = {Breast Cancer Res},
	volume = {19},
	number = {1},
	year = {2017},
	month = {2017 Aug 01},
	pages = {88},
	abstract = {BACKGROUND: Absence of pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) correlates with poor long-term survival in patients with triple negative breast cancer (TNBC). These incomplete treatment responses are likely determined by mechanisms that enable cancer cells to resist being killed. However, the detailed characterization of a drug-resistant cancer cell state in residual TNBC tissue after NACT has remained elusive. AKT1(low) quiescent\&nbsp;cancer cells (QCCs) are a quiescent, epigenetically plastic, and chemotherapy-resistant subpopulation initially identified in experimental cancer models. Here, we asked whether QCCs exist in primary tumors from patients with TNBC and persist after treatment with NACT. METHODS: We obtained pre-treatment biopsy, post-treatment mastectomy, and metastatic specimens from a retrospective cohort of TNBC patients treated with NACT at Massachusetts General Hospital (n = 25). Using quantitative automated immunofluorescence microscopy, QCCs were identified as AKT(low)/H3K9me2(low)/HES1(high) cancer cells using prespecified immunofluorescence intensity thresholds. QCCs were represented in 2D and 3D digital tumor maps and QCC percentage (QCC-P) and QCC cluster index (QCC-CI) were determined for each sample. RESULTS: We showed that QCCs exist as non-random and heterogeneously distributed clusters within primary breast tumors. In addition, these QCC clusters persist after treatment with multi-agent, multi-cycle, neoadjuvant chemotherapy in both residual primary tumors and nodal and distant metastases in patients with triple negative breast cancer. CONCLUSIONS: These first-in-human data potentially qualify AKT1(low) quiescent cancer cells as a non-genetic cell state that persists after neoadjuvant chemotherapy in triple negative breast cancer patients and warrants further study.},
	issn = {1465-542X},
	doi = {10.1186/s13058-017-0877-7},
	url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540189/},
	author = {Kabraji, Sheheryar and Sol{\'e}, Xavier and Huang, Ying and Bango, Clyde and Bowden, Michaela and Bardia, Aditya and Sgroi, Dennis and Loda, Massimo and Ramaswamy, Sridhar}
}
@article {1172346,
	title = {DNA Damage and Repair Biomarkers of Immunotherapy Response},
	journal = {Cancer Discov},
	volume = {7},
	number = {7},
	year = {2017},
	month = {2017 Jul},
	pages = {675-693},
	abstract = {DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.Significance: Only a subset of patients respond to immune checkpoint blockade, and reliable predictive biomarkers of response are needed to guide therapy decisions. DNA repair deficiency is common among tumors, and emerging experimental and clinical evidence suggests that features of genomic instability are associated with response to immune-directed therapies. Cancer Discov; 7(7); 675-93. {\textcopyright}2017 AACR.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-17-0226},
	url = {http://cancerdiscovery.aacrjournals.org/content/7/7/675.long},
	author = {Mouw, Kent W and Goldberg, Michael S and Konstantinopoulos, Panagiotis A and D{\textquoteright}Andrea, Alan D}
}
@article {1172386,
	title = {The EMT regulator ZEB2 is a novel dependency of human and murine acute myeloid leukemia},
	journal = {Blood},
	volume = {129},
	number = {4},
	year = {2017},
	month = {2017 Jan 26},
	pages = {497-508},
	abstract = {Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular pathophysiology. To systematically characterize AML{\textquoteright}s genetic dependencies, we conducted genome-scale short hairpin RNA screens in 17 AML cell lines and analyzed dependencies relative to parallel screens in 199 cell lines of other cancer types. We identified 353 genes specifically required for AML cell proliferation. To validate the in vivo relevance of genetic dependencies observed in human cell lines, we performed a secondary screen in a syngeneic murine AML model driven by the MLL-AF9 oncogenic fusion protein. Integrating the results of these interference RNA screens and additional gene expression data, we identified the transcription factor ZEB2 as a novel AML dependency. ZEB2 depletion impaired the proliferation of both human and mouse AML cells and resulted in aberrant differentiation of human AML cells. Mechanistically, we showed that ZEB2 transcriptionally represses genes that regulate myeloid differentiation, including genes involved in cell adhesion and migration. In addition, we found that epigenetic silencing of the miR-200 family microRNAs affects ZEB2 expression. Our results extend the role of ZEB2 beyond regulating epithelial-mesenchymal transition (EMT) and establish ZEB2 as a novel regulator of AML proliferation and differentiation.},
	keywords = {Animals, Cell Adhesion, Cell Differentiation, Cell Line, Tumor, Cell Movement, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genome-Wide Association Study, Homeodomain Proteins, Humans, Leukemia, Myeloid, Acute, Mice, MicroRNAs, Oncogene Proteins, Fusion, Repressor Proteins, RNA, Small Interfering, Signal Transduction, Transcription, Genetic},
	issn = {1528-0020},
	doi = {10.1182/blood-2016-05-714493},
	url = {http://www.bloodjournal.org/content/129/4/497.long?sso-checked=true},
	author = {Li, Hubo and Mar, Brenton G and Zhang, Huadi and Puram, Rishi V and Vazquez, Francisca and Weir, Barbara A and Hahn, William C and Ebert, Benjamin and Pellman, David}
}
@article {1172321,
	title = {Functional precision cancer medicine-moving beyond pure genomics},
	journal = {Nat Med},
	volume = {23},
	number = {9},
	year = {2017},
	month = {2017 Sep 08},
	pages = {1028-1035},
	abstract = {The essential job of precision medicine is to match the right drugs to the right patients. In cancer, precision medicine has been nearly synonymous with genomics. However, sobering recent studies have generally shown that most patients with cancer who receive genomic testing do not benefit from a genomic precision medicine strategy. Although some call the entire project of precision cancer medicine into question, I suggest instead that the tools employed must be broadened. Instead of relying exclusively on big data measurements of initial conditions, we should also acquire highly actionable functional information by perturbing-for example, with cancer therapies-viable primary tumor cells from patients with cancer.},
	issn = {1546-170X},
	doi = {10.1038/nm.4389},
	url = {https://www.nature.com/nm/journal/v23/n9/full/nm.4389.html},
	author = {Letai, Anthony}
}
@article {1172366,
	title = {Genome-wide identification and characterization of Notch transcription complex-binding sequence-paired sites in leukemia cells},
	journal = {Sci Signal},
	volume = {10},
	number = {477},
	year = {2017},
	month = {2017 May 02},
	abstract = {Notch transcription complexes (NTCs) drive target gene expression by binding to two distinct types of genomic response elements, NTC monomer-binding sites and sequence-paired sites (SPSs) that bind NTC dimers. SPSs are conserved and have been linked to the Notch responsiveness of a few genes. To assess the overall contribution of SPSs to Notch-dependent gene regulation, we determined the DNA sequence requirements for NTC dimerization using a fluorescence resonance energy transfer (FRET) assay and applied insights from these in vitro studies to Notch-"addicted" T cell acute lymphoblastic leukemia (T-ALL) cells. We found that SPSs contributed to the regulation of about a third of direct Notch target genes. Although originally described in promoters, SPSs are present mainly in long-range enhancers, including an enhancer containing a newly described SPS that regulates HES5 expression. Our work provides a general method for identifying SPSs in genome-wide data sets and highlights the widespread role of NTC dimerization in Notch-transformed leukemia cells.},
	issn = {1937-9145},
	doi = {10.1126/scisignal.aag1598},
	url = {http://stke.sciencemag.org/content/10/477/eaag1598.long},
	author = {Severson, Eric and Arnett, Kelly L and Wang, Hongfang and Zang, Chongzhi and Taing, Len and Liu, Hudan and Pear, Warren S and Shirley Liu, X and Blacklow, Stephen C and Aster, Jon C}
}
@article {1172351,
	title = {Immune Escape in Breast Cancer During In Situ to Invasive Carcinoma Transition},
	journal = {Cancer Discov},
	volume = {7},
	number = {10},
	year = {2017},
	month = {2017 Oct},
	pages = {1098-1115},
	abstract = {To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45(+)CD3(+) T cells demonstrated a decrease in CD8(+) signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB(+)CD8(+) T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2(+) breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. {\textcopyright}2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-17-0222},
	url = {http://cancerdiscovery.aacrjournals.org/content/early/2017/06/24/2159-8290.CD-17-0222.long},
	author = {Gil Del Alcazar, Carlos R and Jin Huh, Sung and Ekram, Muhammad B and Trinh, Anne and Liu, Lin L and Beca, Francisco and Zi, Xiaoyuan and Kwak, Minsuk and Bergholtz, Helga and Su, Ying and Ding, Lina and Russnes, Hege G and Richardson, Andrea L and Babski, Kirsten and Min Hui Kim, Elizabeth and McDonnell, Charles H and Wagner, Jon and Rowberry, Ron and Freeman, Gordon J and Dillon, Deborah and Sorlie, Therese and Coussens, Lisa M and Garber, Judy E and Fan, Rong and Bobolis, Kristie and Allred, D Craig and Jeong, Joon and Park, So Yeon and Michor, Franziska and Polyak, Kornelia}
}
@article {1172381,
	title = {MicroRNA therapeutics: towards a new era for the management of cancer and other diseases},
	journal = {Nat Rev Drug Discov},
	volume = {16},
	number = {3},
	year = {2017},
	month = {2017 Mar},
	pages = {203-222},
	abstract = {In just over two decades since the discovery of the first microRNA (miRNA), the field of miRNA biology has expanded considerably. Insights into the roles of miRNAs in development and disease, particularly in cancer, have made miRNAs attractive tools and targets for novel therapeutic approaches. Functional studies have confirmed that miRNA dysregulation is causal in many cases of cancer, with miRNAs acting as tumour suppressors or oncogenes (oncomiRs), and miRNA mimics and molecules targeted at miRNAs (antimiRs) have shown promise in preclinical development. Several miRNA-targeted therapeutics have reached clinical development, including a mimic of the tumour suppressor miRNA miR-34, which reached phase I clinical trials for treating cancer, and antimiRs targeted at miR-122, which reached phase II trials for treating hepatitis. In this article, we describe recent advances in our understanding of miRNAs in cancer and in other diseases and provide an overview of current miRNA therapeutics in the clinic. We also discuss the challenge of identifying the most efficacious therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics.},
	keywords = {Animals, Clinical Trials as Topic, Disease Management, Genetic Therapy, Humans, MicroRNAs, Neoplasms},
	issn = {1474-1784},
	doi = {10.1038/nrd.2016.246},
	author = {Rupaimoole, Rajesha and Slack, Frank J}
}
@article {1172361,
	title = {A molecular portrait of microsatellite instability across multiple cancers},
	journal = {Nat Commun},
	volume = {8},
	year = {2017},
	month = {2017 Jun 06},
	pages = {15180},
	abstract = {Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse \~{}8,000 exomes and \~{}1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.},
	issn = {2041-1723},
	doi = {10.1038/ncomms15180},
	url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467167/},
	author = {Cortes-Ciriano, Isidro and Lee, Sejoon and Park, Woong-Yang and Kim, Tae-Min and Park, Peter J}
}
@article {1172376,
	title = {Necroptosis and Cancer},
	journal = {Trends Cancer},
	volume = {3},
	number = {4},
	year = {2017},
	month = {2017 Apr},
	pages = {294-301},
	abstract = {Necroptosis is a programmed lytic cell death pathway, deregulation of which is linked to various inflammatory disorders. Escape from programmed cell death and inflammation play a significant role in cancer, and therefore, investigating the role of necroptosis in cancer has been of high interest. Necroptosis has been shown to promote cancer metastasis and T cells death. Escape from necroptosis via loss of RIPK3 expression is a feature of some cancers. While necroptosis is a promising novel target for cancer therapies, further investigation into its biological role in carcinogenesis is warranted. In this article, we review the recently-identified interplay points between necroptosis and cancer, and outline major biological questions that require further inquiry on the road to targeting this pathway in cancer.},
	issn = {2405-8033},
	doi = {10.1016/j.trecan.2017.03.002},
	author = {Ayaz Najafov and Chen, Hongbo and Yuan, Junying}
}
@article {1172371,
	title = {p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM},
	journal = {Sci Signal},
	volume = {10},
	number = {476},
	year = {2017},
	month = {2017 Apr 25},
	abstract = {Cellular systems show a wide range of signaling dynamics. Many of these dynamics are highly stereotyped, such as oscillations at a fixed frequency. However, most studies looking at the role of signaling dynamics focus on one or a few cell lines, leaving the diversity of dynamics across tissues or cell lines a largely unexplored question. We focused on the dynamics of the tumor suppressor protein p53, which regulates cell cycle arrest and apoptosis in response to DNA damage. We established live-cell reporters for 12 cancer cell lines expressing wild-type p53 and quantified p53 dynamics in response to double-strand break-inducing DNA damage. In many of the tested cell lines, we found that p53 abundance oscillated in response to ionizing radiation or the DNA-damaging chemotherapeutic neocarzinostatin and that the periodicity of the oscillations was fixed. In other cell lines, p53 abundance dynamically changed in different ways, such as a single broad pulse or a continuous induction. By combining single-cell assays of p53 signaling dynamics, small-molecule screening in live cells, and mathematical modeling, we identified molecules that perturbed p53 dynamics and determined that cell-specific variation in the efficiency of DNA repair and the activity of the kinase ATM (ataxia-telangiectasia mutated) controlled the signaling landscape of p53 dynamics. Because the dynamics of wild-type p53 varied substantially between cell lines, our study highlights the limitation of using one line as a model system and emphasizes the importance of studying the dynamics of other signaling pathways across different cell lines and genetic backgrounds.},
	issn = {1937-9145},
	doi = {10.1126/scisignal.aah6671},
	author = {Stewart-Ornstein, Jacob and Lahav, Galit}
}
@article {1172326,
	title = {p53 pulses lead to distinct patterns of gene expression albeit similar DNA-binding dynamics},
	journal = {Nat Struct Mol Biol},
	year = {2017},
	month = {2017 Aug 21},
	abstract = {The dynamics of transcription factors play important roles in a variety of biological systems. However, the mechanisms by which these dynamics are decoded into different transcriptional responses are not well understood. Here we focus on the dynamics of the tumor-suppressor protein p53, which exhibits a series of pulses in response to DNA damage. We performed time course RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) measurements to determine how p53 oscillations are linked with gene expression genome wide. We discovered multiple distinct patterns of gene expression in response to p53 pulses. Surprisingly, p53-binding dynamics were uniform across all genomic loci, even for genes that exhibited distinct mRNA dynamics. Using a mathematical model, supported by additional experimental measurements in response to sustained p53 input, we determined that p53 binds to and activates transcription of its target genes uniformly, whereas post-transcriptional mechanisms are responsible for the differences in gene expression dynamics.},
	issn = {1545-9985},
	doi = {10.1038/nsmb.3452},
	url = {https://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.3452.html},
	author = {Hafner, Antonina and Stewart-Ornstein, Jacob and Purvis, Jeremy E and Forrester, William C and Bulyk, Martha L and Lahav, Galit}
}
@article {1172341,
	title = {Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution},
	journal = {Cancer Res},
	volume = {77},
	number = {14},
	year = {2017},
	month = {2017 Jul 15},
	pages = {3908-3921},
	abstract = {The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908-21. {\textcopyright}2017 AACR.},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-16-2871},
	author = {Chakrabarti, Shaon and Michor, Franziska}
}
@article {1172331,
	title = {Synergistic activity and heterogeneous acquired resistance of combined MDM2 and MEK inhibition in KRAS mutant cancers},
	journal = {Oncogene},
	year = {2017},
	month = {2017 Aug 07},
	abstract = {There are currently no effective targeted therapies for KRAS mutant cancers. Therapeutic strategies that combine MEK inhibitors with agents that target apoptotic pathways may be a promising therapeutic approach. We investigated combining MEK and MDM2 inhibitors as a potential treatment strategy for KRAS mutant non-small cell lung cancers (NSCLC) and colorectal carcinomas that harbor wild-type TP53. The combination of pimasertib (MEK inhibitor) and SAR405838 (MDM2 inhibitor) was synergistic and induced the expression of PUMA and BIM, led to apoptosis and growth inhibition in vitro, and tumor regression in vivo. Acquired resistance to the combination commonly resulted from the acquisition of TP53 mutations, conferring complete resistance to MDM2 inhibition. In contrast, resistant clones exhibited marked variability in sensitivity to MEK inhibition, which significantly impacted sensitivity to subsequent treatment with alternative MEK inhibitor-based combination therapies. These results highlight both the potential promise and limitations of combining MEK and MDM2 inhibitors for treatment of KRAS mutant NSCLC and colorectal cancers.Oncogene advance online publication, 7 August 2017; doi:10.1038/onc.2017.258.},
	issn = {1476-5594},
	doi = {10.1038/onc.2017.258},
	author = {Hata, A N and Rowley, S and Archibald, H L and Gomez-Caraballo, M and Siddiqui, F M and Ji, F and Jung, J and Light, M and Lee, J S and Debussche, L and Sidhu, S and Sadreyev, R I and Watters, J and Engelman, J. A.}
}
@article {1123096,
	title = {Epigenetic plasticity and the hallmarks of cancer},
	journal = {Science},
	volume = {357},
	number = {6348},
	year = {2017},
	pages = {eaal2380},
	abstract = {Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while also facilitating appropriate responses to developmental or environmental cues. Genetic, environmental, or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or "plastic" states may allow stochastic oncogene activation or nonphysiologic cell fate transitions. Whereas many stochastic events will be inconsequential "passengers," some will confer a fitness advantage to a cell and be selected as "drivers." We review the broad roles played by epigenetic aberrations in tumor initiation and evolution and their potential to give rise to all classic hallmarks of cancer.},
	url = {http://science.sciencemag.org/content/357/6348/eaal2380},
	author = {William A. Flavahan and Elizabeth Gaskell and Bradley E. Bernstein}
}
@article {1118476,
	title = {The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation},
	journal = {Sci Transl Med},
	volume = {9},
	number = {391},
	year = {2017},
	month = {2017 May 24},
	abstract = {Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.},
	issn = {1946-6242},
	doi = {10.1126/scitranslmed.aal4682},
	url = {http://stm.sciencemag.org/content/9/391/eaal4682.short},
	author = {Kodack, David P and Askoxylakis, Vasileios and Ferraro, Gino B and Sheng, Qing and Badeaux, Mark and Goel, Shom and Qi, Xiaolong and Shankaraiah, Ram and Cao, Z Alexander and Ramjiawan, Rakesh R and Bezwada, Divya and Patel, Bhushankumar and Song, Yongchul and Costa, Carlotta and Naxerova, Kamila and Wong, Christina S F and Kloepper, Jonas and Das, Rita and Tam, Angela and Tanboon, Jantima and Duda, Dan G and Miller, C Ryan and Siegel, Marni B and Anders, Carey K and Sanders, Melinda and Estrada, Monica V and Schlegel, Robert and Arteaga, Carlos L and Brachtel, Elena and Huang, Alan and Fukumura, Dai and Engelman, Jeffrey A and Jain, Rakesh K}
}
@article {1118456,
	title = {Decoupling genetics, lineages, and microenvironment in IDH-mutant gliomas by single-cell RNA-seq},
	journal = {Science},
	volume = {355},
	number = {6332},
	year = {2017},
	month = {2017 Mar 31},
	abstract = {Tumor subclasses differ according to the genotypes and phenotypes of malignant cells as well as the composition of the tumor microenvironment (TME). We dissected these influences in isocitrate dehydrogenase (IDH)-mutant gliomas by combining 14,226 single-cell RNA sequencing (RNA-seq) profiles from 16 patient samples with bulk RNA-seq profiles from 165 patient samples. Differences in bulk profiles between IDH-mutant astrocytoma and oligodendroglioma can be primarily explained by distinct TME and signature genetic events, whereas both tumor types share similar developmental hierarchies and lineages of glial differentiation. As tumor grade increases, we find enhanced proliferation of malignant cells, larger pools of undifferentiated glioma cells, and an increase in macrophage over microglia expression programs in TME. Our work provides a unifying model for IDH-mutant gliomas and a general framework for dissecting the differences among human tumor subclasses.},
	issn = {1095-9203},
	doi = {10.1126/science.aai8478},
	url = {http://science.sciencemag.org/content/355/6332/eaai8478.long},
	author = {Venteicher, Andrew S and Itay Tirosh and Hebert, Christine and Yizhak, Keren and Neftel, Cyril and Filbin, Mariella G and Hovestadt, Volker and Escalante, Leah E and Shaw, McKenzie L and Rodman, Christopher and Gillespie, Shawn M and Dionne, Danielle and Luo, Christina C and Ravichandran, Hiranmayi and Mylvaganam, Ravindra and Mount, Christopher and Onozato, Maristela L and Nahed, Brian V and Wakimoto, Hiroaki and Curry, William T and Iafrate, A John and Rivera, Miguel N and Frosch, Matthew P and Golub, Todd R and Brastianos, Priscilla K and Getz, Gad and Patel, Anoop P and Monje, Michelle and Cahill, Daniel P and Rozenblatt-Rosen, Orit and Louis, David N and Bernstein, Bradley E and Regev, Aviv and Suv{\`a}, Mario L}
}
@article {1118451,
	title = {Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers},
	journal = {Cancer Discov},
	volume = {7},
	number = {2},
	year = {2017},
	month = {2017 Feb},
	pages = {202-217},
	abstract = {Luminal breast cancers are typically estrogen receptor-positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50\% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.

SIGNIFICANCE: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202-17. {\textcopyright}2016 AACR.See related commentary by Sears and Gray, p. 131This article is highlighted in the In This Issue feature, p. 115.},
	issn = {2159-8290},
	doi = {10.1158/2159-8290.CD-16-0520},
	author = {Olsen, Sarah Naomi and Wronski, Ania and Casta{\~n}o, Zafira and Dake, Benjamin and Malone, Clare and De Raedt, Thomas and Enos, Miriam and DeRose, Yoko S and Zhou, Wenhui and Guerra, Stephanie and Loda, Massimo and Welm, Alana and Partridge, Ann H and McAllister, Sandra S and Kuperwasser, Charlotte and Cichowski, Karen}
}
@article {1118446,
	title = {Origins of lymphatic and distant metastases in human colorectal cancer},
	journal = {Science},
	volume = {357},
	number = {6346},
	year = {2017},
	month = {2017 Jul 07},
	pages = {55-60},
	abstract = {The spread of cancer cells from primary tumors to regional lymph nodes is often associated with reduced survival. One prevailing model to explain this association posits that fatal, distant metastases are seeded by lymph node metastases. This view provides a mechanistic basis for the TNM staging system and is the rationale for surgical resection of tumor-draining lymph nodes. Here we examine the evolutionary relationship between primary tumor, lymph node, and distant metastases in human colorectal cancer. Studying 213 archival biopsy samples from 17 patients, we used somatic variants in hypermutable DNA regions to reconstruct high-confidence phylogenetic trees. We found that in 65\% of cases, lymphatic and distant metastases arose from independent subclones in the primary tumor, whereas in 35\% of cases they shared common subclonal origin. Therefore, two different lineage relationships between lymphatic and distant metastases exist in colorectal cancer.},
	issn = {1095-9203},
	doi = {10.1126/science.aai8515},
	author = {Naxerova, Kamila and Reiter, Johannes G and Brachtel, Elena and Lennerz, Jochen K and van de Wetering, Marc and Rowan, Andrew and Cai, Tianxi and Clevers, Hans and Swanton, Charles and Martin A. Nowak and Elledge, Stephen J and Jain, Rakesh K}
}
@article {1053556,
	title = {Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages},
	journal = {Nature},
	volume = {543},
	number = {7645},
	year = {2017},
	month = {2017 Mar 16},
	pages = {428-432},
	abstract = {Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.},
	issn = {1476-4687},
	doi = {10.1038/nature21409},
	url = {http://www.nature.com/nature/journal/v543/n7645/full/nature21409.html},
	author = {Guerriero, Jennifer L and Sotayo, Alaba and Ponichtera, Holly E and Castrillon, Jessica A and Pourzia, Alexandra L and Schad, Sara and Johnson, Shawn F and Carrasco, Ruben D and Lazo, Suzan and Bronson, Roderick T. and Davis, Scott P and Lobera, Mercedes and Nolan, Michael A and Letai, Anthony}
}
@article {1041416,
	title = {PI3K signaling in cancer: beyond AKT},
	journal = {Curr Opin Cell Biol},
	volume = {45},
	year = {2017},
	month = {2017 Mar 23},
	pages = {62-71},
	abstract = {The phosphoinositide 3-kinase (PI3K) signaling pathway is one of the most frequently altered pathways in human cancer and has a critical role in driving tumor initiation and progression. Although PI3K and its lipid product phosphatidylinositol-3,4,5-trisphosphate (PIP3) have been shown to activate multiple downstream signaling proteins, the vast majority of studies have focused on the protein kinase AKT as the dominant effector of PI3K signaling. However, recent studies have demonstrated many contexts under which other PIP3-dependent signaling proteins critically contribute to cancer progression, illustrating the importance of understanding AKT-independent signaling downstream of PI3K. Here, we highlight three PI3K-dependent, but AKT-independent, signaling branches that have recently been shown to have important roles in promoting phenotypes associated with malignancy. First, the PDK1-mTORC2-SGK axis can substitute for AKT in survival, migration, and growth signaling and has emerged as a major mechanism of resistance to PI3K and AKT inhibitors. Second, Rac signaling mediates the reorganization of the actin cytoskeleton to regulate cancer cell migration, invasion, and metabolism. Finally, the TEC family kinase BTK has a critical role in B cell function and malignancy and represents a recent example of an effective therapeutic target in cancer. These mechanisms highlight how understanding PI3K-dependent, but AKT-independent, signaling mechanisms that drive cancer progression will be crucial for the development of novel and more effective approaches for targeting the PI3K pathway for therapeutic benefit in cancer.},
	issn = {1879-0410},
	doi = {10.1016/j.ceb.2017.02.007},
	url = {http://www.sciencedirect.com/science/article/pii/S0955067417300236?via\%3Dihub},
	author = {Lien, Evan C and Dibble, Christian C and Toker, Alex}
}
@article {1018816,
	title = {Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer},
	journal = {Cancer Discovery},
	volume = {7},
	number = {4},
	year = {2017},
	pages = {1-9},
	abstract = {\&nbsp;Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using\&nbsp;in vitro\&nbsp;and\&nbsp;in vivo\&nbsp;metabolic profiling of TNBC cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the\&nbsp;de novo\&nbsp;pyrimidine synthesis pathway. Pharmacologic inhibition of\&nbsp;de novo\&nbsp;pyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the\&nbsp;de novo\&nbsp;pyrimidine synthesis pathway, induces regression of TNBC xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of TNBC.SIGNIFICANCE:\&nbsp;The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of\&nbsp;de novo\&nbsp;pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of\&nbsp;de novo\&nbsp;pyrimidine synthesis, to sensitize TNBC cells to chemotherapy.Ludwig Cancer Research coverage:http://www.ludwigcancerresearch.org/news/vulnerability-triple-negative-breast-cancer-could-improve-treatment-outcomes\&nbsp;\&nbsp;\&nbsp;},
	url = {http://cancerdiscovery.aacrjournals.org/content/early/2017/02/28/2159-8290.CD-16-0611},
	author = {Brown, Kristin K and Spinelli, Jessica B and Asara, John M and Toker, Alex}
}
@article {975811,
	title = {Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.},
	journal = {Science},
	volume = {355},
	number = {6322},
	year = {2017},
	month = {2017 Jan 20},
	abstract = {Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8(+) T cells, and increased expression of cell proliferation markers. Different types of SCNAs predict the proliferation and immune signatures, implying distinct underlying mechanisms. Using published data from two clinical trials of immune checkpoint blockade therapy for metastatic melanoma, we found that tumor aneuploidy inversely correlates with patient survival. Together with other tumor characteristics such as tumor mutational load, aneuploidy may thus help identify patients most likely to respond to immunotherapy.},
	issn = {1095-9203},
	doi = {10.1126/science.aaf8399},
	author = {Davoli, Teresa and Uno, Hajime and Wooten, Eric C and Elledge, Stephen J}
}
@article {965781,
	title = {Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state.},
	journal = {Mol Syst Biol},
	volume = {13},
	number = {1},
	year = {2017},
	month = {2017 Jan 09},
	pages = {905},
	abstract = {Treatment of BRAF-mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live-cell imaging, single-cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug-adapted cells up-regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug-na{\"\i}ve state within 9\&nbsp;days of drug withdrawal. Transcriptional profiling of cell lines and human tumors implicates a c-Jun/ECM/FAK/Src cascade in de-differentiation in about one-third of cell lines studied; drug-induced changes in c-Jun and NGFR levels are also observed in xenograft and human tumors. Drugs targeting the c-Jun/ECM/FAK/Src cascade as well as BET bromodomain inhibitors increase the maximum effect (Emax) of RAF/MEK kinase inhibitors by promoting cell killing. Thus, analysis of reversible drug resistance at a single-cell level identifies signaling pathways and inhibitory drugs missed by assays that focus on cell populations.},
	issn = {1744-4292},
	doi = {10.15252/msb.20166796},
	author = {Fallahi-Sichani, Mohammad and Becker, Verena and Izar, Benjamin and Baker, Gregory J and Lin, Jia-Ren and Boswell, Sarah A and Shah, Parin and Rotem, Asaf and Garraway, Levi A and Sorger, Peter K}
}
@article {1221666,
	title = {Dynamics of CDKN1A in Single Cells Defined by an Endogenous Fluorescent Tagging Toolkit},
	journal = {Cell Rep},
	volume = {14},
	number = {7},
	year = {2016},
	month = {2016 Feb 23},
	pages = {1800-1811},
	abstract = {Observing the endogenous abundance, localization, and dynamics of proteins in mammalian cells is crucial to understanding their function and behavior. Currently, there is no systematic approach for the fluorescent tagging of endogenous loci. Here, we used Cas9-catalyzed DNA breaks, short homology arms, and a family of donor plasmids to establish endogenous Fluorescent tagging (eFlut): a low-cost and efficient approach to generating endogenous proteins with fluorescent labels. We validated this protocol on multiple proteins in several cell lines and species and applied our tools to study the cell-cycle inhibitor CDKN1A in single cells. We uncover heterogeneity in the timing and rate of CDKN1A induction post-DNA damage and show that this variability is post-transcriptionally regulated, depends on cell-cycle position, and has long-term consequences for cellular proliferation. The tools developed in this study should support widespread study of the dynamics and localization of diverse proteins in mammalian cells.},
	keywords = {Animals, Bacterial Proteins, Catalase, Cell Cycle Checkpoints, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, DNA Damage, Dogs, Endonucleases, Epithelial Cells, Fluorescent Dyes, Gene Expression Regulation, Genes, Reporter, HEK293 Cells, Hepatocytes, Humans, Luminescent Proteins, Madin Darby Canine Kidney Cells, Mice, NIH 3T3 Cells, Plasmids, Single-Cell Analysis, Staining and Labeling, Transfection},
	issn = {2211-1247},
	doi = {10.1016/j.celrep.2016.01.045},
	author = {Stewart-Ornstein, Jacob and Lahav, Galit}
}
@article {975761,
	title = {Functional genomics reveals that tumors with activating phosphoinositide 3-kinase mutations are dependent on accelerated protein turnover.},
	journal = {Genes Dev},
	volume = {30},
	number = {24},
	year = {2016},
	month = {2016 Dec 15},
	pages = {2684-2695},
	abstract = {Activating mutations in the phosphoinositide 3-kinase (PI3K) signaling pathway are frequently identified in cancer. To identify pathways that support PI3K oncogenesis, we performed a genome-wide RNAi screen in isogenic cell lines harboring wild-type or mutant PIK3CA to search for PI3K synthetic-lethal (SL) genes. A combined analysis of these results with a meta-analysis of two other large-scale RNAi screening data sets in PI3K mutant cancer cell lines converged on ribosomal protein translation and proteasomal protein degradation as critical nononcogene dependencies for PI3K-driven tumors. Genetic or pharmacologic inhibition of either pathway alone, but not together, selectively killed PI3K mutant tumor cells in an mTOR-dependent manner. The expression of ribosomal and proteasomal components was significantly up-regulated in primary human colorectal tumors harboring PI3K pathway activation. Importantly, a PI3K SL gene signature containing the top hits of the SL genes identified in our meta-analysis robustly predicted overall patient survival in colorectal cancer, especially among patients with tumors with an activated PI3K pathway. These results suggest that disruption of protein turnover homeostasis via ribosome or proteasome inhibition may be a novel treatment strategy for PI3K mutant human tumors.},
	issn = {1549-5477},
	doi = {10.1101/gad.290122.116},
	author = {Davoli, Teresa and Mengwasser, Kristen E and Duan, Jingjing and Chen, Ting and Christensen, Camilla and Wooten, Eric C and Anselmo, Anthony N and Li, Mamie Z and Wong, Kwok-Kin and Kahle, Kristopher T and Elledge, Stephen J}
}
@article {965786,
	title = {Cyclic Immunofluorescence (CycIF), A Highly Multiplexed Method for Single-cell Imaging.},
	journal = {Curr Protoc Chem Biol},
	volume = {8},
	number = {4},
	year = {2016},
	month = {2016 Dec 07},
	pages = {251-264},
	abstract = {Cyclic Immunofluorescence (CycIF) is a public-domain method for performing highly multiplexed immunofluorescence imaging using a conventional epifluorescence microscope. It uses simple reagents and existing antibodies to construct images with up to 30 channels by sequential 4- to 6-channel imaging followed by fluorophore inactivation. Three variant methods are described, the most generally useful of which involves staining fixed cells with antibodies directly conjugated to Alexa Fluor dyes and imaging in four colors, inactivating fluorophores using a mild base in the presence of hydrogen peroxide and light, and then performing another round of staining and imaging. Cell morphology is preserved through multiple rounds of CycIF, and signal-to-noise ratios appear to increase. Unlike antibody-stripping methods, CycIF is gentle and optimized for monolayers of cultured cells. A second protocol involves indirect immunofluorescence and a third enables chemical inactivation of genetically encoded fluorescent proteins, allowing multiplex immunofluorescence to be combined with live-cell analysis of cells expressing fluorescent reporter proteins. {\textcopyright} 2016 by John Wiley \& Sons, Inc.},
	issn = {2160-4762},
	doi = {10.1002/cpch.14},
	author = {Lin, Jia-Ren and Fallahi-Sichani, Mohammad and Chen, Jia-Yun and Sorger, Peter K}
}
@article {925316,
	title = {AKT Inhibition Promotes Nonautonomous Cancer Cell Survival.},
	journal = {Mol Cancer Ther},
	volume = {15},
	number = {1},
	year = {2016},
	month = {2016 Jan},
	pages = {142-53},
	abstract = {Small molecule inhibitors of AKT (v-akt murine thymoma viral oncogene homolog) signaling are being evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with subtherapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multiscale, molecular snapshot of this "AKT(low)" cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously upregulate a host of other proteins and metabolites posttranscriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication.},
	issn = {1538-8514},
	doi = {10.1158/1535-7163.MCT-15-0414},
	author = {Sol{\'e}, Xavier and Alves, Cleidson P and Dey-Guha, Ipsita and Ritsma, Laila and Boukhali, Myriam and Lee, Ju H and Chowdhury, Joeeta and Ross, Kenneth N and Haas, Wilhelm and Vasudevan, Shobha and Ramaswamy, Sridhar}
}
@article {924556,
	title = {Differential Glutamate Metabolism in Proliferating and Quiescent Mammary Epithelial Cells.},
	journal = {Cell Metab},
	volume = {23},
	number = {5},
	year = {2016},
	month = {2016 May 10},
	pages = {867-80},
	abstract = {Mammary epithelial cells transition between periods of proliferation and quiescence during development, menstrual cycles, and pregnancy, and as a result of oncogenic transformation. Utilizing an organotypic 3D tissue culture model coupled with quantitative metabolomics and proteomics, we identified significant differences in glutamate utilization between proliferating and quiescent cells. Relative to quiescent cells, proliferating cells catabolized more glutamate via transaminases to couple non-essential amino acid (NEAA) synthesis to α-ketoglutarate generation and tricarboxylic acid (TCA) cycle anaplerosis. As cells transitioned to quiescence, glutamine consumption and transaminase expression were reduced, while glutamate dehydrogenase (GLUD) was induced, leading to decreased NEAA synthesis. Highly proliferative human tumors display high transaminase and low GLUD expression, suggesting that proliferating cancer cells couple glutamine consumption to NEAA synthesis to promote biosynthesis. These findings describe a competitive and partially redundant relationship between transaminases and GLUD, and they reveal how coupling of glutamate-derived carbon and nitrogen metabolism can be regulated to support cell proliferation.},
	issn = {1932-7420},
	doi = {10.1016/j.cmet.2016.03.016},
	author = {Coloff, Jonathan L and Murphy, J Patrick and Braun, Craig R and Harris, Isaac S and Shelton, Laura M and Kami, Kenjiro and Gygi, Steven P and Selfors, Laura M and Brugge, Joan S}
}
@article {924561,
	title = {Establishment of patient-derived tumor xenograft models of epithelial ovarian cancer for pre-clinical evaluation of novel therapeutics.},
	journal = {Clin Cancer Res},
	year = {2016},
	month = {2016 Aug 29},
	abstract = {PURPOSE: Ovarian cancer is the leading cause of death from gynecologic malignancy in the United States, with high rates of recurrence and eventual resistance to cytotoxic chemotherapy. Model systems that allow for accurate and reproducible target discovery and validation are needed to support further drug development in this disease.

EXPERIMENTAL DESIGN: Clinically-annotated patient-derived xenograft (PDX) models were generated from tumor cells isolated from the ascites or pleural fluid of patients undergoing clinical procedures. Models were characterized by immunohistochemistry and by molecular analyses. Each PDX was luciferized to allow for reproducible in vivo assessment of intraperitoneal tumor burden by bioluminescent imaging (BLI). Plasma assays for CA125 and human LINE-1 were developed as secondary tests of in vivo disease burden.

RESULTS: 14 clinically annotated and molecularly characterized luciferized ovarian PDX models were generated. Luciferized PDX models retain fidelity to both the non-luciferized PDX and the original patient tumor, as demonstrated by immunohistochemistry, array CGH, and targeted and whole-exome sequencing analyses. Models demonstrated diversity in specific genetic alterations and activation of PI3K signaling pathway members. Response of luciferized PDX models to standard of care therapy could be reproducibly monitored by BLI or plasma markers.

CONCLUSIONS: We describe the establishment of a collection of 14 clinically annotated and molecularly characterized luciferized ovarian PDX models in which orthotopic tumor burden in the intraperitoneal space can be followed by standard and reproducible methods. This collection is well-suited as a platform for proof-of-concept efficacy and biomarker studies and for validation of novel therapeutic strategies in ovarian cancer.},
	issn = {1078-0432},
	doi = {10.1158/1078-0432.CCR-16-1237},
	author = {Liu, Joyce F and Palakurthi, Sangeetha and Zeng, Qing and Zhou, Shan and Ivanova, Elena and Huang, Wei and Zervantonakis, Ioannis K and Selfors, Laura M and Shen, Yiping and Pritchard, Colin C and Zheng, Mei and Adleff, Vilmos and Papp, Eniko and Piao, Huiying and Novak, Marian and Fotheringham, Susan and Wulf, Gerburg and English, Jessie and Kirschmeier, Paul T and Velculescu, Victor E and Paweletz, Cloud P and Mills, Gordon B and Livingston, David M and Brugge, Joan S and Matulonis, Ursula A and Drapkin, Ronny}
}
@article {924551,
	title = {The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis.},
	journal = {Clin Cancer Res},
	year = {2016},
	month = {2016 Jun 21},
	abstract = {PURPOSE: To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer.

EXPERIMENTAL DESIGN: Expression data from primary breast cancer biopsies for 1419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics including response to NAC were collected. Scores for 125 previously published breast cancer-related gene expression signatures were calculated for each tumor.

RESULTS: Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pCR to NAC. To distinguish {\textquoteright}proliferation-associated{\textquoteright} from {\textquoteright}proliferation-independent{\textquoteright} signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation-associated: 90.5\% (38/42) in ER+/HER2- and 63.3\% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2- breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, EGFR), and {\textquoteright}stemness{\textquoteright} phenotypes.

CONCLUSIONS: Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2- breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pCR in ER+/HER2- breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes.},
	issn = {1078-0432},
	doi = {10.1158/1078-0432.CCR-16-0471},
	author = {Stover, Daniel G and Coloff, Jonathan L and Barry, William T and Brugge, Joan S and Winer, Eric P and Selfors, Laura M}
}
@article {924506,
	title = {Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing},
	journal = {Cell},
	volume = {165},
	number = {3},
	year = {2016},
	month = {2016 Apr 21},
	pages = {631-42},
	abstract = {Many chemotherapeutic drugs kill only a fraction of cancer cells, limiting their efficacy. We used live-cell imaging to investigate the role of p53 dynamics in fractional killing of colon cancer cells in response to chemotherapy. We found that both surviving and dying cells reach similar levels of p53, indicating that cell death is not determined by a fixed p53 threshold. Instead, a cell{\textquoteright}s probability of death depends on the time and levels of p53. Cells must reach a threshold level of p53 to execute apoptosis, and this threshold increases with time. The increase in p53 apoptotic threshold is due to drug-dependent induction of anti-apoptotic genes, predominantly in the inhibitors of apoptosis (IAP) family. Our study underlines the importance of measuring the dynamics of key players in response to chemotherapy to determine mechanisms of resistance and optimize the timing of combination therapy.},
	keywords = {Antineoplastic Agents, Apoptosis, Cell Line, Tumor, cisplatin, Drug Resistance, Neoplasm, Humans, Inhibitor of Apoptosis Proteins, Tumor Suppressor Protein p53, Up-Regulation},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2016.03.025},
	author = {Paek, Andrew L and Liu, Julia C and Loewer, Alexander and Forrester, William C and Lahav, Galit}
}
@article {924531,
	title = {Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.},
	journal = {Science},
	volume = {352},
	number = {6282},
	year = {2016},
	month = {2016 Apr 8},
	pages = {189-96},
	abstract = {To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.},
	keywords = {Base Sequence, Cell Communication, Cell Cycle, Drug Resistance, Neoplasm, Endothelial Cells, Genomics, Humans, Immunotherapy, Lymphocyte Activation, Melanoma, Microphthalmia-Associated Transcription Factor, Neoplasm Metastasis, RNA, Sequence Analysis, RNA, Single-Cell Analysis, Skin Neoplasms, Stromal Cells, T-Lymphocytes, Transcriptome, Tumor Microenvironment},
	issn = {1095-9203},
	doi = {10.1126/science.aad0501},
	author = {Itay Tirosh and Izar, Benjamin and Prakadan, Sanjay M and Wadsworth, Marc H and Treacy, Daniel and Trombetta, John J and Rotem, Asaf and Rodman, Christopher and Lian, Christine and Murphy, George and Fallahi-Sichani, Mohammad and Dutton-Regester, Ken and Lin, Jia-Ren and Cohen, Ofir and Shah, Parin and Lu, Diana and Genshaft, Alex S and Hughes, Travis K and Ziegler, Carly G K and Kazer, Samuel W and Gaillard, Aleth and Kolb, Kellie E and Villani, Alexandra-Chlo{\'e} and Johannessen, Cory M and Andreev, Aleksandr Y and Van Allen, Eliezer M and Bertagnolli, Monica and Sorger, Peter K and Sullivan, Ryan J and Flaherty, Keith T and Frederick, Dennie T and Jan{\'e}-Valbuena, Judit and Yoon, Charles H and Rozenblatt-Rosen, Orit and Shalek, Alex K and Regev, Aviv and Garraway, Levi A}
}
@article {924526,
	title = {Distinct evolutionary paths to TKI resistance in NSCLC.},
	journal = {Cell Cycle},
	year = {2016},
	month = {2016 Aug 23},
	issn = {1551-4005},
	doi = {10.1080/15384101.2016.1221024},
	author = {Niederst, Matthew J and Engelman, Jeffrey A and Hata, Aaron N}
}
@article {924536,
	title = {Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs.},
	journal = {Nat Methods},
	volume = {13},
	number = {6},
	year = {2016},
	month = {2016 Jun},
	pages = {521-7},
	abstract = {Drug sensitivity and resistance are conventionally quantified by IC50 or Emax values, but these metrics are highly sensitive to the number of divisions taking place over the course of a response assay. The dependency of IC50 and Emax on division rate creates artefactual correlations between genotype and drug sensitivity, while obscuring valuable biological insights and interfering with biomarker discovery. We derive alternative small molecule drug-response metrics that are insensitive to division number. These are based on estimation of the magnitude of drug-induced growth rate inhibition (GR) using endpoint or time-course assays. We show that GR50 and GRmax are superior to conventional metrics for assessing the effects of small molecule drugs in dividing cells. Moreover, adopting GR metrics requires only modest changes in experimental protocols. We expect GR metrics to improve the study of cell signaling and growth using small molecules and biologics and to facilitate the discovery of drug-response biomarkers and the identification of drugs effective against specific patient-derived tumor cells.},
	issn = {1548-7105},
	doi = {10.1038/nmeth.3853},
	author = {Hafner, Marc and Niepel, Mario and Chung, Mirra and Sorger, Peter K}
}
@article {924516,
	title = {Longitudinal, label-free, quantitative tracking of cell death and viability in a 3D tumor model with OCT.},
	journal = {Sci Rep},
	volume = {6},
	year = {2016},
	month = {2016},
	pages = {27017},
	abstract = {Three-dimensional in vitro tumor models are highly useful tools for studying tumor growth and treatment response of malignancies such as ovarian cancer. Existing viability and treatment assessment assays, however, face shortcomings when applied to these large, complex, and heterogeneous culture systems. Optical coherence tomography (OCT) is a noninvasive, label-free, optical imaging technique that can visualize live cells and tissues over time with subcellular resolution and millimeters of optical penetration depth. Here, we show that OCT is capable of carrying out high-content, longitudinal assays of 3D culture treatment response. We demonstrate the usage and capability of OCT for the dynamic monitoring of individual and combination therapeutic regimens in vitro, including both chemotherapy drugs and photodynamic therapy (PDT) for ovarian cancer. OCT was validated against the standard LIVE/DEAD Viability/Cytotoxicity Assay in small tumor spheroid cultures, showing excellent correlation with existing standards. Importantly, OCT was shown to be capable of evaluating 3D spheroid treatment response even when traditional viability assays failed. OCT 3D viability imaging revealed synergy between PDT and the standard-of-care chemotherapeutic carboplatin that evolved over time. We believe the efficacy and accuracy of OCT in vitro drug screening will greatly contribute to the field of cancer treatment and therapy evaluation.},
	issn = {2045-2322},
	doi = {10.1038/srep27017},
	author = {Jung, Yookyung and Klein, Oliver J and Wang, Hequn and Evans, Conor L}
}
@article {924511,
	title = {Schedule-dependent interaction between anticancer treatments},
	journal = {Science},
	volume = {351},
	number = {6278},
	year = {2016},
	month = {2016 Mar 11},
	pages = {1204-8},
	abstract = {The oncogene MDMX is overexpressed in many cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene product MDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However, we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathway and cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinct phases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitude oscillations. The response to DNA damage was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase, depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellular states is important for designing an optimal schedule of dual-drug administration.},
	keywords = {Antineoplastic Agents, Apoptosis, DNA Damage, Gene Knockdown Techniques, Humans, MCF-7 Cells, Molecular Imaging, Neoplasms, Proto-Oncogene Proteins c-mdm2, RNA, Small Interfering, Signal Transduction, Time Factors, Tumor Suppressor Protein p53},
	issn = {1095-9203},
	doi = {10.1126/science.aac5610},
	author = {Chen, Sheng-Hong and Forrester, William and Lahav, Galit}
}
@article {924476,
	title = {How autophagy both activates and inhibits cellular senescence.},
	journal = {Autophagy},
	volume = {12},
	number = {5},
	year = {2016},
	month = {2016 May 3},
	pages = {898-9},
	abstract = {Autophagy and cellular senescence are stress responses essential for homeostasis. While recent studies indicate a genetic relationship between autophagy and senescence, whether autophagy acts positively or negatively on senescence is still subject to debate. Although autophagy was originally recognized as a nonspecific lysosomal degradation pathway (general autophagy), increasing evidence supports a selective form of autophagy that mediates the degradation of specific targets (selective autophagy). Our recent study revealed distinctive roles of selective autophagy and general autophagy in the regulation of senescence, at least in part resolving apparently contradictory reports regarding the relationship between these 2 important homeostatic stress responses.},
	issn = {1554-8635},
	doi = {10.1080/15548627.2015.1121361},
	author = {Kang, Chanhee and Elledge, Stephen J}
}
@article {924486,
	title = {An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.},
	journal = {Nat Genet},
	volume = {48},
	number = {3},
	year = {2016},
	month = {2016 Mar},
	pages = {265-72},
	abstract = {Translocation events are frequent in cancer and may create chimeric fusions or {\textquoteright}regulatory rearrangements{\textquoteright} that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps highlight distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in alternate ACC lineages.},
	keywords = {Carcinoma, Adenoid Cystic, Cell Line, Tumor, Cell Lineage, Chromatin, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Humans, Oncogene Proteins v-myb, Oncogene Proteins, Fusion, Transcription Factors, Translocation, Genetic, Tumor Suppressor Proteins},
	issn = {1546-1718},
	doi = {10.1038/ng.3502},
	author = {Drier, Yotam and Cotton, Matthew J and Williamson, Kaylyn E and Gillespie, Shawn M and Ryan, Russell J H and Kluk, Michael J and Carey, Christopher D and Rodig, Scott J and Sholl, Lynette M and Afrogheh, Amir H and Faquin, William C and Queimado, Lurdes and Qi, Jun and Wick, Michael J and El-Naggar, Adel K and Bradner, James E and Moskaluk, Christopher A and Aster, Jon C and Knoechel, Birgit and Bernstein, Bradley E}
}
@article {924461,
	title = {PHD3 Loss in Cancer Enables Metabolic Reliance on Fatty Acid Oxidation via Deactivation of ACC2.},
	journal = {Mol Cell},
	volume = {63},
	number = {6},
	year = {2016},
	month = {2016 Sep 15},
	pages = {1006-20},
	abstract = {While much research has examined the use of glucose and glutamine by tumor cells, many cancers instead prefer to metabolize fats. Despite the pervasiveness of this phenotype, knowledge of pathways that drive fatty acid oxidation (FAO) in cancer is limited. Prolyl hydroxylase domain proteins hydroxylate substrate proline residues and have been linked to fuel switching. Here, we reveal that PHD3 rapidly triggers repression of FAO in response to nutrient abundance via hydroxylation of acetyl-coA carboxylase 2 (ACC2). We find that PHD3 expression is strongly decreased in subsets of cancer including acute myeloid leukemia (AML) and is linked to a reliance on fat catabolism regardless of external nutrient cues. Overexpressing PHD3 limits FAO via regulation of ACC2 and consequently impedes leukemia cell proliferation. Thus, loss of PHD3 enables greater utilization of fatty acids but may also serve as a metabolic and therapeutic liability by indicating cancer cell susceptibility to FAO inhibition.},
	issn = {1097-4164},
	doi = {10.1016/j.molcel.2016.08.014},
	author = {German, Natalie J and Yoon, Haejin and Yusuf, Rushdia Z and Murphy, J Patrick and Finley, Lydia W S and Laurent, Ga{\"e}lle and Haas, Wilhelm and Satterstrom, F Kyle and Guarnerio, Jlenia and Zaganjor, Elma and Santos, Daniel and Pandolfi, Pier Paolo and Beck, Andrew H and Gygi, Steven P and Scadden, David T and Kaelin, William G and Haigis, Marcia C}
}
@article {924471,
	title = {Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumors.},
	journal = {Nat Genet},
	volume = {48},
	number = {6},
	year = {2016},
	month = {2016 Jun},
	pages = {600-6},
	abstract = {Alterations in DNA repair pathways are common in tumors and can result in characteristic mutational signatures; however, a specific mutational signature associated with somatic alterations in the nucleotide- excision repair (NER) pathway has not yet been identified. Here we examine the mutational processes operating in urothelial cancer, a tumor type in which the core NER gene ERCC2 is significantly mutated. Analysis of three independent urothelial tumor cohorts demonstrates a strong association between somatic ERCC2 mutations and the activity of a mutational signature characterized by a broad spectrum of base changes. In addition, we note an association between the activity of this signature and smoking that is independent of ERCC2 mutation status, providing genomic evidence of tobacco-related mutagenesis in urothelial cancer. Together, these analyses identify an NER-related mutational signature and highlight the related roles of DNA damage and subsequent DNA repair in shaping tumor mutational landscape.},
	issn = {1546-1718},
	doi = {10.1038/ng.3557},
	author = {Kim, Jaegil and Mouw, Kent W and Polak, Paz and Braunstein, Lior Z and Kamburov, Atanas and Tiao, Grace and Kwiatkowski, David J and Rosenberg, Jonathan E and Van Allen, Eliezer M and D{\textquoteright}Andrea, Alan D and Getz, Gad}
}
@article {924466,
	title = {Suppression by TFR cells leads to durable and selective inhibition of B cell effector function.},
	journal = {Nat Immunol},
	year = {2016},
	month = {2016 Oct 03},
	abstract = {Follicular regulatory T cells (TFR cells) inhibit follicular helper T cell (TFH cell)-mediated antibody production. The mechanisms by which TFR cells exert their key immunoregulatory functions are largely unknown. Here we found that TFR cells induced a distinct suppressive state in TFH cells and B cells, in which effector transcriptional signatures were maintained but key effector molecules and metabolic pathways were suppressed. The suppression of B cell antibody production and metabolism by TFR cells was durable and persisted even in the absence of TFR cells. This durable suppression was due in part to epigenetic changes. The cytokine IL-21 was able to overcome TFR cell-mediated suppression and inhibited TFR cells and stimulated B cells. By determining mechanisms of TFR cell-mediated suppression, we have identified methods for modulating the function of TFR cells and antibody production.},
	issn = {1529-2916},
	doi = {10.1038/ni.3578},
	author = {Sage, Peter T and Ron-Harel, Noga and Juneja, Vikram R and Sen, Debattama R and Maleri, Seth and Sungnak, Waradon and Kuchroo, Vijay K and Haining, W Nicholas and Chevrier, Nicolas and Haigis, Marcia and Sharpe, Arlene H}
}
@article {924501,
	title = {USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1.},
	journal = {Genes Dev},
	volume = {30},
	number = {15},
	year = {2016},
	month = {2016 Aug 1},
	pages = {1718-30},
	abstract = {The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular degradative mechanisms that mediate the turnover of complementary repertoires of intracellular proteomes. Simultaneously activating both UPS and autophagy might provide a powerful strategy for the clearance of misfolded proteins. However, it is not clear whether UPS and autophagy can be controlled by a common regulatory mechanism. K48 deubiquitination by USP14 is known to inhibit UPS. Here we show that USP14 regulates autophagy by negatively controlling K63 ubiquitination of Beclin 1. Furthermore, we show that activation of USP14 by Akt-mediated phosphorylation provides a mechanism for Akt to negatively regulate autophagy by promoting K63 deubiquitination. Our study suggests that Akt-regulated USP14 activity modulates both proteasomal degradation and autophagy through controlling K48 and K63 ubiquitination, respectively. Therefore, regulation of USP14 provides a mechanism for Akt to control both proteasomal and autophagic degradation. We propose that inhibition of USP14 may provide a strategy to promote both UPS and autophagy for developing novel therapeutics targeting neurodegenerative diseases.},
	issn = {1549-5477},
	doi = {10.1101/gad.285122.116},
	author = {Xu, Daichao and Shan, Bing and Sun, Huawang and Xiao, Juan and Zhu, Kezhou and Xie, Xingxing and Li, Xingyan and Liang, Wei and Lu, Xiaojuan and Qian, Lihui and Yuan, Junying}
}
@article {924456,
	title = {Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia.},
	journal = {Cell},
	volume = {167},
	number = {1},
	year = {2016},
	month = {2016 Sep 22},
	pages = {171-186.e15},
	abstract = {While acute myeloid leukemia (AML) comprises many disparate genetic subtypes, one shared hallmark is the arrest of leukemic myeloblasts at an immature and self-renewing stage of development. Therapies that overcome differentiation arrest represent a powerful treatment strategy. We leveraged the observation that the majority of AML, despite their genetically heterogeneity, share in the expression of HoxA9, a gene normally downregulated during myeloid differentiation. Using a conditional HoxA9 model system, we performed a high-throughput phenotypic screen and defined compounds that overcame differentiation blockade. Target identification led to the unanticipated discovery that inhibition of the enzyme dihydroorotate dehydrogenase (DHODH) enables myeloid differentiation in human and mouse AML models. In\&nbsp;vivo, DHODH inhibitors reduced leukemic cell burden, decreased levels of leukemia-initiating cells, and improved survival. These data demonstrate the role of DHODH as a metabolic regulator of differentiation and point to its inhibition as a strategy for overcoming differentiation blockade in AML.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2016.08.057},
	author = {Sykes, David B and Kfoury, Youmna S and Mercier, Fran{\c c}ois E and Wawer, Mathias J and Law, Jason M and Haynes, Mark K and Lewis, Timothy A and Schajnovitz, Amir and Jain, Esha and Lee, Dongjun and Meyer, Hanna and Pierce, Kerry A and Tolliday, Nicola J and Waller, Anna and Ferrara, Steven J and Eheim, Ashley L and Stoeckigt, Detlef and Maxcy, Katrina L and Cobert, Julien M and Bachand, Jacqueline and Szekely, Brian A and Mukherjee, Siddhartha and Sklar, Larry A and Kotz, Joanne D and Clish, Clary B and Sadreyev, Ruslan I and Clemons, Paul A and Janzer, Andreas and Schreiber, Stuart L and Scadden, David T}
}
@article {924546,
	title = {Reengineering the Tumor Microenvironment to Alleviate Hypoxia and Overcome Cancer Heterogeneity.},
	journal = {Cold Spring Harb Perspect Med},
	year = {2016},
	month = {2016 Sep 23},
	abstract = {Solid tumors consist of cancer cells and stromal cells, including resident and transiting immune cells-all ensconced in an extracellular matrix (ECM)-nourished by blood vessels and drained by lymphatic vessels. The microenvironment constituents are abnormal and heterogeneous in morphology, phenotype, and physiology. Such irregularities include an inefficient tumor vascular network comprised of leaky and compressed vessels, which impair blood flow and oxygen delivery. Low oxygenation in certain tumor regions-or focal hypoxia-is a mediator of cancer progression, metastasis, immunosuppression, and treatment resistance. Thus, repairing an abnormal and heterogeneous microenvironment-and hypoxia in particular-can significantly improve treatments of solid tumors. Here, we summarize two strategies to reengineer the tumor microenvironment (TME)-vessel normalization and decompression-that can alleviate hypoxia. In addition, we discuss how these two strategies alone and in combination with each other-or other therapeutic strategies-may overcome the challenges posed by cancer heterogeneity.},
	issn = {2157-1422},
	doi = {10.1101/cshperspect.a027094},
	author = {Martin, John D and Fukumura, Dai and Duda, Dan G and Boucher, Yves and Jain, Rakesh K}
}
@article {924491,
	title = {Spatial proximity to fibroblasts impacts molecular features and therapeutic sensitivity of breast cancer cells influencing clinical outcomes.},
	journal = {Cancer Res},
	year = {2016},
	month = {2016 Sep 26},
	abstract = {Using a 3D co-culture model, we identified significant sub-type-specific changes in gene expression, metabolic, and therapeutic sensitivity profiles of breast cancer cells in contact with cancer-associated fibroblasts (CAFs). CAF-induced gene expression signatures predicted clinical outcome and immune-related differences in the microenvironment. We found that fibroblasts strongly protect carcinoma cells from lapatinib, attributable to its reduced accumulation in carcinoma cells and an elevated apoptotic threshold. Fibroblasts from normal breast tissues and stromal cultures of brain metastases of breast cancer had similar effects as CAFs. Using synthetic lethality approaches, we identified molecular pathways whose inhibition sensitizes HER2+ breast cancer cells to lapatinib both in vitro and in vivo including JAK2/STAT3 and hyaluronic acid. Neoadjuvant lapatinib therapy in HER2+ breast tumors lead to a significant increase of phospho-STAT3+ cancer cells and a decrease in the spatial proximity of proliferating (Ki67+) cells to CAFs impacting therapeutic responses. Our studies identify CAF-induced physiologically and clinically relevant changes in cancer cells and offer novel approaches for overcoming microenvironment-mediated therapeutic resistance.},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-16-1457},
	author = {Marusyk, Andriy and Tabassum, Doris and Janiszewska, Michalina and Place, Andrew and Trinh, Anne and Rozhok, Andrii I and Pyne, Saumyadipta and Guerriero, Jennifer and Shu, Shaokun and Ekram, Muhammad and Ishkin, Alexander and Cahill, Daniel P and Nikolsky, Yuri and Chan, Timothy A and Rimawi, Mothaffar F and Hilsenbeck, Susan G and Schiff, Rachel and Osborne, C Kent and Letai, Anthony and Polyak, Kornelia}
}
@article {817701,
	title = {Mitochondria and Cancer.},
	journal = {Cell},
	volume = {166},
	number = {3},
	year = {2016},
	month = {2016 Jul 28},
	pages = {555-66},
	abstract = {Mitochondria are bioenergetic, biosynthetic, and signaling organelles that are integral in stress sensing to allow for cellular adaptation to the environment. Therefore, it is not surprising that mitochondria are important mediators of tumorigenesis, as this process requires flexibility to adapt to cellular and environmental alterations in addition to cancer treatments. Multiple aspects of mitochondrial biology beyond bioenergetics support transformation, including mitochondrial biogenesis and turnover, fission and fusion dynamics, cell death susceptibility, oxidative stress regulation, metabolism, and signaling. Thus, understanding mechanisms of mitochondrial function during tumorigenesis will be critical for the next generation of cancer therapeutics.},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2016.07.002},
	author = {Vyas, Sejal and Zaganjor, Elma and Haigis, Marcia C}
}
@article {689026,
	title = {Glutathione biosynthesis is a metabolic vulnerability in PI(3)K/Akt-driven breast cancer.},
	journal = {Nat Cell Biol},
	year = {2016},
	month = {2016 Apr 18},
	abstract = {Cancer cells often select for mutations that enhance signalling through pathways that promote anabolic metabolism. Although the PI(3)K/Akt signalling pathway, which is frequently dysregulated in breast cancer, is a well-established regulator of central glucose metabolism and aerobic glycolysis, its regulation of other metabolic processes required for tumour growth is not well defined. Here we report that in mammary epithelial cells, oncogenic PI(3)K/Akt stimulates glutathione (GSH) biosynthesis by stabilizing and activating NRF2 to upregulate the GSH biosynthetic genes. Increased NRF2 stability is dependent on the Akt-mediated accumulation of p21(Cip1/WAF1) and GSK-3β inhibition. Consistently, in human breast tumours, upregulation of NRF2 targets is associated with PI(3)K pathway mutation status and oncogenic Akt activation. Elevated GSH biosynthesis is required for PI(3)K/Akt-driven resistance to oxidative stress, initiation of tumour spheroids, and anchorage-independent growth. Furthermore, inhibition of GSH biosynthesis with buthionine sulfoximine synergizes with cisplatin to selectively induce tumour regression in PI(3)K pathway mutant breast cancer cells, both in vitro and in vivo. Our findings provide insight into GSH biosynthesis as a metabolic vulnerability associated with PI(3)K pathway mutant breast cancers.},
	issn = {1476-4679},
	doi = {10.1038/ncb3341},
	author = {Lien, Evan C and Lyssiotis, Costas A and Juvekar, Ashish and Hu, Hai and Asara, John M and Cantley, Lewis C and Toker, Alex}
}
@article {642436,
	title = {Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.},
	journal = {Nat Med},
	year = {2016},
	month = {2016 Feb 1},
	abstract = {Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.},
	issn = {1546-170X},
	doi = {10.1038/nm.4040},
	author = {Hata, Aaron N and Niederst, Matthew J and Archibald, Hannah L and Gomez-Caraballo, Maria and Siddiqui, Faria M and Mulvey, Hillary E and Maruvka, Yosef E and Ji, Fei and Bhang, Hyo-Eun C and Krishnamurthy Radhakrishna, Viveksagar and Siravegna, Giulia and Hu, Haichuan and Raoof, Sana and Lockerman, Elizabeth and Kalsy, Anuj and Lee, Dana and Keating, Celina L and Ruddy, David A and Damon, Leah J and Crystal, Adam S and Costa, Carlotta and Piotrowska, Zofia and Bardelli, Alberto and Iafrate, Anthony J and Sadreyev, Ruslan I and Stegmeier, Frank and Getz, Gad and Sequist, Lecia V and Faber, Anthony C and Engelman, Jeffrey A}
}
@article {625891,
	title = {Insulator dysfunction and oncogene activation in IDH mutant gliomas.},
	journal = {Nature},
	volume = {529},
	number = {7584},
	year = {2016},
	month = {2016 Jan 7},
	pages = {110-4},
	abstract = {Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5{\textquoteright}-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (CTCF)-binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression.},
	issn = {1476-4687},
	doi = {10.1038/nature16490},
	author = {Flavahan, William A and Drier, Yotam and Liau, Brian B and Gillespie, Shawn M and Venteicher, Andrew S and Stemmer-Rachamimov, Anat O and Suv{\`a}, Mario L and Bernstein, Bradley E}
}
@article {625866,
	title = {Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.},
	journal = {Nature},
	year = {2016},
	month = {2016 Jan 6},
	abstract = {Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.},
	issn = {1476-4687},
	doi = {10.1038/nature16508},
	author = {Shu, Shaokun and Lin, Charles Y and He, Housheng Hansen and Witwicki, Robert M and Tabassum, Doris P and Roberts, Justin M and Janiszewska, Michalina and Jin Huh, Sung and Liang, Yi and Ryan, Jeremy and Doherty, Ernest and Mohammed, Hisham and Guo, Hao and Stover, Daniel G and Ekram, Muhammad B and Peluffo, Guillermo and Brown, Jonathan and D{\textquoteright}Santos, Clive and Krop, Ian E and Dillon, Deborah and McKeown, Michael and Ott, Christopher and Qi, Jun and Ni, Min and Rao, Prakash K and Duarte, Melissa and Wu, Shwu-Yuan and Chiang, Cheng-Ming and Anders, Lars and Young, Richard A and Winer, Eric P and Letai, Antony and Barry, William T and Carroll, Jason S and Long, Henry W and Brown, Myles and Shirley Liu, X and Meyer, Clifford A and Bradner, James E and Polyak, Kornelia}
}
@article {925321,
	title = {A mechanism for asymmetric cell division resulting in proliferative asynchronicity.},
	journal = {Mol Cancer Res},
	volume = {13},
	number = {2},
	year = {2015},
	month = {2015 Feb},
	pages = {223-30},
	abstract = {UNLABELLED: All cancers contain an admixture of rapidly and slowly proliferating cancer cells. This proliferative heterogeneity complicates the diagnosis and treatment of patients with cancer because slow proliferators are hard to eradicate, can be difficult to detect, and may cause disease relapse sometimes years after apparently curative treatment. While clonal selection theory explains the presence and evolution of rapid proliferators within cancer cell populations, the circumstances and molecular details of how slow proliferators are produced is not well understood. Here, a β1-integrin/FAK/mTORC2/AKT1-associated signaling pathway is discovered that can be triggered for rapidly proliferating cancer cells to undergo asymmetric cell division and produce slowly proliferating AKT1(low) daughter cells. In addition, evidence indicates that the proliferative output of this signaling cascade involves a proteasome-dependent degradation process mediated by the E3 ubiquitin ligase TTC3. These findings reveal that proliferative heterogeneity within cancer cell populations, in part, is produced through a targetable signaling mechanism, with potential implications for understanding cancer progression, dormancy, and therapeutic resistance.

IMPLICATIONS: These findings provide a deeper understanding of the proliferative heterogeneity that exists in the tumor environment and highlight the importance of designing future therapies against multiple proliferative contexts. VISUAL OVERVIEW: A proposed mechanism for producing slowly proliferating cancer cells. http://mcr.aacrjournals.org/content/early/2015/01/09/1541-7786.MCR-14-0474/F1.large.jpg.},
	keywords = {Asymmetric Cell Division, Clonal Evolution, Genetic Heterogeneity, HCT116 Cells, Humans, MCF-7 Cells, Neoplasms, Proto-Oncogene Proteins c-akt, Signal Transduction, Tumor Microenvironment},
	issn = {1557-3125},
	doi = {10.1158/1541-7786.MCR-14-0474},
	author = {Dey-Guha, Ipsita and Alves, Cleidson P and Yeh, Albert C and Yeh, Albert C and Sole, Xavier and Darp, Revati and Ramaswamy, Sridhar}
}
@article {925326,
	title = {Mechanisms of Cancer Cell Dormancy--Another Hallmark of Cancer?},
	journal = {Cancer Res},
	volume = {75},
	number = {23},
	year = {2015},
	month = {2015 Dec 1},
	pages = {5014-22},
	abstract = {Disease relapse in cancer patients many years after clinical remission, often referred to as cancer dormancy, is well documented but remains an incompletely understood phenomenon on the biologic level. Recent reviews have summarized potential models that can explain this phenomenon, including angiogenic, immunologic, and cellular dormancy. We focus on mechanisms of cellular dormancy as newer biologic insights have enabled better understanding of this process. We provide a historical context, synthesize current advances in the field, and propose a mechanistic framework that treats cancer cell dormancy as a dynamic cell state conferring a fitness advantage to an evolving malignancy under stress. Cellular dormancy appears to be an active process that can be toggled through a variety of signaling mechanisms that ultimately downregulate the RAS/MAPK and PI(3)K/AKT pathways, an ability that is preserved even in cancers that constitutively depend on these pathways for their growth and survival. Just as unbridled proliferation is a key hallmark of cancer, the ability of cancer cells to become quiescent may be critical to evolving malignancies, with implications for understanding cancer initiation, progression, and treatment resistance.},
	keywords = {Animals, Humans, Neoplasms},
	issn = {1538-7445},
	doi = {10.1158/0008-5472.CAN-15-1370},
	author = {Yeh, Albert C and Ramaswamy, Sridhar}
}
@article {924541,
	title = {Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis.},
	journal = {Mol Syst Biol},
	volume = {11},
	number = {3},
	year = {2015},
	month = {2015 Mar},
	pages = {797},
	abstract = {Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAF(V) (600E) melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti-tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single-cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax~<<~1). Among these cascades, we identify a role for JNK/c-Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.},
	keywords = {Apoptosis, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Drug Synergism, Humans, Indoles, MAP Kinase Signaling System, Melanoma, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides},
	issn = {1744-4292},
	doi = {10.15252/msb.20145877},
	author = {Fallahi-Sichani, Mohammad and Moerke, Nathan J and Niepel, Mario and Zhang, Tinghu and Gray, Nathanael S and Sorger, Peter K}
}
@article {924481,
	title = {The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.},
	journal = {Science},
	volume = {349},
	number = {6255},
	year = {2015},
	month = {2015 Sep 25},
	pages = {aaa5612},
	abstract = {Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-κB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.},
	keywords = {Aging, Animals, Ataxia Telangiectasia Mutated Proteins, Autophagy, Brain, Cell Aging, Cell Cycle, Cells, Cultured, Cyclin-Dependent Kinase Inhibitor p16, DNA Damage, Fibroblasts, GATA4 Transcription Factor, Gene Expression Profiling, Humans, Inflammation, Interleukin-1alpha, Mice, Mice, Inbred C57BL, MicroRNAs, NF-kappa B, Phenotype, Promoter Regions, Genetic, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Tumor Suppressor Protein p53},
	issn = {1095-9203},
	doi = {10.1126/science.aaa5612},
	author = {Kang, Chanhee and Xu, Qikai and Martin, Timothy D and Li, Mamie Z and Demaria, Marco and Aron, Liviu and Lu, Tao and Yankner, Bruce A and Campisi, Judith and Elledge, Stephen J}
}
@article {924496,
	title = {The mathematics of cancer: integrating quantitative models.},
	journal = {Nat Rev Cancer},
	volume = {15},
	number = {12},
	year = {2015},
	month = {2015 Dec},
	pages = {730-45},
	abstract = {Mathematical modelling approaches have become increasingly abundant in cancer research. The complexity of cancer is well suited to quantitative approaches as it provides challenges and opportunities for new developments. In turn, mathematical modelling contributes to cancer research by helping to elucidate mechanisms and by providing quantitative predictions that can be validated. The recent expansion of quantitative models addresses many questions regarding tumour initiation, progression and metastases as well as intra-tumour heterogeneity, treatment responses and resistance. Mathematical models can complement experimental and clinical studies, but also challenge current paradigms, redefine our understanding of mechanisms driving tumorigenesis and shape future research in cancer biology.},
	keywords = {Animals, Disease Progression, Humans, Models, Biological, Models, Theoretical, Neoplasms, Prognosis},
	issn = {1474-1768},
	doi = {10.1038/nrc4029},
	author = {Altrock, Philipp M and Liu, Lin L and Michor, Franziska}
}
@article {595481,
	title = {Raman technologies in cancer diagnostics.},
	journal = {Analyst},
	year = {2015},
	month = {2015 Nov 5},
	abstract = {Despite significant effort, cancer still remains a leading cause of death worldwide. In order to reduce its burden, the development and improvement of noninvasive strategies for early detection and diagnosis of cancer are urgently needed. Raman spectroscopy, an optical technique that relies on inelastic light scattering arising from molecular vibrations, is one such strategy, as it can noninvasively probe cancerous markers using only endogenous contrast. In this review, spontaneous, coherent and surface enhanced Raman spectroscopies and imaging, as well as the fundamental principles governing the successful use of these techniques, are discussed. Methods for spectral data analysis are also highlighted. Utilization of the discussed Raman techniques for the detection and diagnosis of cancer in vitro, ex vivo and in vivo is described. The review concludes with a discussion of the future directions of Raman technologies, with particular emphasis on their clinical translation.},
	issn = {1364-5528},
	doi = {10.1039/c5an01786f},
	author = {Austin, Lauren A and Osseiran, Sam and Evans, Conor L}
}
@article {589786,
	title = {Drug-induced death signaling strategy rapidly predicts cancer response to chemotherapy.},
	journal = {Cell},
	volume = {160},
	number = {5},
	year = {2015},
	month = {2015 Feb 26},
	pages = {977-89},
	abstract = {There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient{\textquoteright}s living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.},
	keywords = {Carcinoma, Non-Small-Cell Lung, Cell Death, Cell Line, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Mitochondria, Neoplasms, Ovarian Neoplasms, Precision Medicine, Signal Transduction},
	issn = {1097-4172},
	doi = {10.1016/j.cell.2015.01.042},
	author = {Montero, Joan and Sarosiek, Kristopher A and DeAngelo, Joseph D and Maertens, Oph{\'e}lia and Ryan, Jeremy and Ercan, Dalia and Piao, Huiying and Horowitz, Neil S and Berkowitz, Ross S. and Matulonis, Ursula and J{\"a}nne, Pasi A and Amrein, Philip C and Cichowski, Karen and Drapkin, Ronny and Letai, Anthony}
}
@article {567486,
	title = {Cancer: The enemy of my enemy is my friend.},
	journal = {Nature},
	volume = {527},
	year = {2015},
	pages = {170-171},
	abstract = {Reactive oxygen species have been viewed as stress-inducing molecules that promote cancer initiation. But new evidence indicates that oxidative stress can be beneficial {\textemdash} inhibiting the spread of a cancer to other sites.},
	author = {Harris, Isaac S and Brugge, Joan S}
}
@article {548556,
	title = {Cytotoxic T lymphocyte antigen-4 and immune checkpoint blockade},
	journal = {Journal of Clinical Investigation},
	volume = {125},
	number = {9},
	year = {2015},
	pages = {3377-3383},
	abstract = {The relationship between cancer and the immune system is complex and provides unique therapeutic opportunities. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a regulatory molecule that suppresses T cell effector function following initial activation by costimulatory signals. Fully human monoclonal antibodies targeting CTLA-4 have been shown to increase T cell function and antitumor responses in patients with advanced metastatic melanoma. Responses observed with such immune checkpoint therapy can follow a different pattern from that seen with cytotoxic chemotherapy or targeted therapy and may continue after therapy is discontinued. In addition, the toxicities that are associated with anti{\textendash}CTLA-4 therapy may differ from those of conventional therapies and consist of inflammatory events in parts of the body that do not contain cancerous cells. Early recognition of these inflammatory events and intervention is important, and the identification of predictive biomarkers continues to be an unfulfilled need in the field of immunotherapy. Combinatorial approaches with targeted therapies, radiation therapy, chemotherapy, or other immune checkpoint agonists/antagonists have the potential to increase the efficacy of CTLA-4 blockade.},
	author = {Buchbinder, E and Hodi, FS}
}
@article {548536,
	title = {Degradation of HK2 by chaperone-mediated autophagy promotes metabolic catastrophe and cell death.},
	journal = {Journal of Cell Biology},
	volume = {210},
	number = {5},
	year = {2015},
	pages = {705-16},
	abstract = {Hexokinase II (HK2), a key enzyme involved in glucose metabolism, is regulated by growth factor signaling and is required for initiation and maintenance of tumors. Here we show that metabolic stress triggered by perturbation of receptor tyrosine kinase FLT3 in non{\textendash}acute myeloid leukemia cells sensitizes cancer cells to autophagy inhibition and leads to excessive activation of chaperone-mediated autophagy (CMA). Our data demonstrate that FLT3 is an important sensor of cellular nutritional state and elucidate the role and molecular mechanism of CMA in metabolic regulation and mediating cancer cell death. Importantly, our proteome analysis revealed that HK2 is a CMA substrate and that its degradation by CMA is regulated by glucose availability. We reveal a new mechanism by which excessive activation of CMA may be exploited pharmacologically to eliminate cancer cells by inhibiting both FLT3 and autophagy. Our study delineates a novel pharmacological strategy to promote the degradation of HK2 in cancer cells.},
	author = {Xia, HG and Najafov, A and Geng, J and Galan-Acosta, L and Han, X and Guo, Y and Shan, B and Zhang, Y. and Norberg, E and Zhang, T and Pan, L and Liu, J. and Coloff, JL and Ofengeim, D and Zhu, H and Wu, K and Cai, Y and Yates, JR and Zhu, Z. and Yuan, J and Vakifahmetoglu-Norberg, H}
}
@article {548561,
	title = {MERIT40 Is an Akt Substrate that Promotes Resolution of DNA DAmage Induced by Chemotherapy},
	journal = {Cell Reports},
	volume = {11},
	number = {9},
	year = {2015},
	pages = {1358-1366},
	abstract = {Resistance to cytotoxic chemotherapy drugs, including doxorubicin, is a significant obstacle to the effective treatment of breast cancer. Here, we have identified a mechanism by which the PI3K/Akt pathway mediates resistance to doxorubicin. In addition to inducing DNA damage, doxorubicin triggers sustained activation of Akt signaling in breast cancer cells. We show that Akt contributes to chemotherapy resistance such that PI3K or Akt inhibitors sensitize cells to doxorubicin. We identify MERIT40, a component of the BRCA1-A DNA damage repair complex, as an Akt substrate that is phosphorylated following doxorubicin treatment. MERIT40 phosphorylation facilitates assembly of the BRCA1-A complex in response to DNA damage and contributes to DNA repair\&nbsp;and cell survival following doxorubicin treatment. Finally, MERIT40 phosphorylation in human breast cancers is associated with estrogen receptor positivity. Our findings suggest that combination therapy with PI3K or Akt inhibitors and doxorubicin may constitute a successful strategy for overcoming chemotherapy resistance.
\&nbsp;},
	author = {Brown, KK and Montaser-Kouhsari, L and Beck, A H and Toker, A}
}
@article {924521,
	title = {PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies.},
	journal = {Nature},
	volume = {514},
	number = {7521},
	year = {2014},
	month = {2014 Oct 9},
	pages = {247-51},
	abstract = {The polycomb repressive complex 2 (PRC2) exerts oncogenic effects in many tumour types. However, loss-of-function mutations in PRC2 components occur in a subset of haematopoietic malignancies, suggesting that this complex plays a dichotomous and poorly understood role in cancer. Here we provide genomic, cellular, and mouse modelling data demonstrating that the polycomb group gene SUZ12 functions as tumour suppressor in PNS tumours, high-grade gliomas and melanomas by cooperating with mutations in NF1. NF1 encodes a Ras GTPase-activating protein (RasGAP) and its loss drives cancer by activating Ras. We show that SUZ12 loss potentiates the effects of NF1 mutations by amplifying Ras-driven transcription through effects on chromatin. Importantly, however, SUZ12 inactivation also triggers an epigenetic switch that sensitizes these cancers to bromodomain inhibitors. Collectively, these studies not only reveal an unexpected connection between the PRC2 complex, NF1 and Ras, but also identify a promising epigenetic-based therapeutic strategy that may be exploited for a variety of cancers.},
	keywords = {Animals, Azepines, Cell Death, Chromatin, Disease Models, Animal, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Glioma, Humans, Melanoma, Mice, Mitogen-Activated Protein Kinase Kinases, Neoplasms, Nerve Sheath Neoplasms, Neurofibromin 1, Nuclear Proteins, Polycomb Repressive Complex 2, ras Proteins, Transcription Factors, Transcription, Genetic, Triazoles, Tumor Suppressor Proteins},
	issn = {1476-4687},
	doi = {10.1038/nature13561},
	author = {De Raedt, Thomas and Beert, Eline and Pasmant, Eric and Luscan, Armelle and Brems, Hilde and Ortonne, Nicolas and Helin, Kristian and Hornick, Jason L and Mautner, Victor and Kehrer-Sawatzki, Hildegard and Clapp, Wade and Bradner, James and Vidaud, Michel and Upadhyaya, Meena and Legius, Eric and Cichowski, Karen}
}
@article {589621,
	title = {Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma},
	journal = {Science},
	volume = {344},
	year = {2014},
	pages = {1396-401},
	abstract = {Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a continuum of stemness-related expression states that enabled us to identify putative regulators of stemness in vivo. Finally, we show that established glioblastoma subtype classifiers are variably expressed across individual cells within a tumor and demonstrate the potential prognostic implications of such intratumoral heterogeneity. Thus, we reveal previously unappreciated heterogeneity in diverse regulatory programs central to glioblastoma biology, prognosis, and therapy.},
	author = {Patel, AP and Tirosh, I and Shalek, AK and Gillespie, SM and Wakimoto, H and Cahill, DP and Nahed, BV and Curry, WT and Martuza, RL and Louis, DN and Rozenblatt-Rosen, O and Suva, ML and Regev, A and Bernstein, BE}
}
@article {1172136,
	title = {Rapid, shallow breathing after Ascaris suum antigen inhalation: role of vagus nerves},
	journal = {J Appl Physiol Respir Environ Exerc Physiol},
	volume = {42},
	number = {1},
	year = {1977},
	month = {1977 Jan},
	pages = {101-6},
	abstract = {In five treadmill-exercising, unsedated dogs, we studied the effect of inhaled Ascaris suum antigen aerosols on minute volume of ventilation (VE), respiratory frequency (f), tidal volume (VT), total pulmonary resistance (RL), and dynamic pulmonary compliance (CLdyn), before and during cooling of the vagus nerves. With the vagi warm, inhaled antigen increased VE (mean + 62\%; P less than 0.01)by increasing f (mean + 180\%; P less than 0.01), despite a decrease in VT (mean - 42\%; P less than 0.01). RL increased (mean + 170\%; P less than 0.001) and CLdyn decreased (mean - 43\%; P less than 0.005). With the vagi cool, inhaled antigen no longer affected VE, f, or VT (P greater than 0.5), although RL still increased and CLdyn still decreased. Inhalation of a bronchodilator, terbutaline, prevented the broncho-constriction induced by antigen but did not prevent the ventilatory response. We conclude that vagal afferent pathways mediate the ventilatory response to inhaled antigen and suggest that the primary stimulus for this response is not airway narrowing.},
	keywords = {Animals, Antigens, Ascaris, Asthma, Carbon Dioxide, Cold Temperature, Disease Models, Animal, Dogs, Hydrogen-Ion Concentration, Oxygen, Respiration, Terbutaline, Tidal Volume, Vagus Nerve},
	issn = {0161-7567},
	author = {Cotton, D J and Bleecker, E R and Fischer, S P and Graf, P D and Gold, W M and Nadel, J A}
}
@article {1172206,
	title = {Letter: Stability of aspirin in combination with propoxyphene hydrochloride and propoxyphene napsylate},
	journal = {N Engl J Med},
	volume = {294},
	number = {16},
	year = {1976},
	month = {1976 Apr 15},
	pages = {907},
	keywords = {Aspirin, Dextropropoxyphene, Drug Compounding, Drug Stability},
	issn = {0028-4793},
	doi = {10.1056/NEJM197604152941625},
	author = {Kaul, A F and Harshfield, J C}
}
@article {1172246,
	title = {Metabolism of dihalomethanes to formaldehyde and inorganic halide. I. In vitro studies},
	journal = {Drug Metab Dispos},
	volume = {4},
	number = {4},
	year = {1976},
	month = {1976 Jul-Aug},
	pages = {357-61},
	abstract = {Metabolism of dihalomethanes by rat liver cytosol fractions yielded formaldehyde and inorganic halide as products. Loss of metabolic activity resulting from dialysis of the cytosol was restored with glutathione. Cysteine could not substitute for GSH. No other cofactor was found to be required for activity. The optimum conditions for this biotransformation with respect to time, temperature, protein concentration, and pH were determined. Rates of metabolism of dihalomethanes showed the following order: CH2i2 greater than CH2Br2 congruent to CH2BrCi greater than CH2Ci2. Administration of the enzyme inducer, phenobarbital, to rats did not alter this metabolic pathway nor did repeated administration of CH2Br2 or CH2Ci2 change the rate of metabolism. The enzyme catalyzing this reaction was localized in the liver. Compounds known to serve as substrates for various GSH transferases inhibited the reaction as did those capable of interacting with sulfhydryl groups.},
	keywords = {Anaerobiosis, Animals, Brain, Bromides, Chlorides, Cysteine, Cytosol, Formaldehyde, Glutathione, Hydrocarbons, Halogenated, Iodides, Kinetics, Liver, Methane, Organ Specificity, Rats},
	issn = {0090-9556},
	author = {Ahmed, A E and Anders, M W}
}
@article {1172191,
	title = {Quantitative fractionation of alkaline phosphatase isoenzymes according to their thermostability},
	journal = {Clin Chem},
	volume = {22},
	number = {1},
	year = {1976},
	month = {1976 Jan},
	pages = {42-8},
	abstract = {Continuous monitoring of heat denaturation of a mixture of alkaline phosphatase isoenzymes at 60 degrees C and pH 7.5 permits the simultaneous direct identification and quantitation of three isoenzymes: the placental isoenzyme, the L-phenylalanine-sensitive intestinal isoenzyme, and the liver isoenzyme (hepatocytic). The isoenzyme that is principally of bone origin cannot be identified as such without the help of other diagnostic aids and the patient{\textquoteright}s medical history. All human tissues contain alkaline phosphatase, many organs more than one of the isoenzymes. Liver alkaline phosphatase, which constitutes 40-50\% of normal serum alkaline phosphatase activity, was measured in the serum of persons with various liver diseases. Its activity exceeded normal in all types of liver disease; in 80\% of cases this increase was accompanied by increased gamma-glutamyl-transferase activity, but the quantitative correlationship (r = 0.54) was not as good as expected if both enzymes come from the same source and are indices of liver dieases. Liver alkaline phosphatase activity increases in the blood early in liver disease, before most liver tests show abnormalities. The other major isoenzyme of normal serum probably represents a mixture of isoenzymes from bone and reticulo-endothelial and vascular tissues, which all contain the same "very heat-labile" alkaline phosphatase. Cord blood and children{\textquoteright}s sera contain mostly this very heat-labile isoenzyme.},
	keywords = {Alkaline Phosphatase, Blood, Bone and Bones, Duodenum, Female, gamma-Glutamyltransferase, Humans, Hydrogen-Ion Concentration, Isoenzymes, Liver, Liver Diseases, Male, Phosphates, Placenta, Pregnancy, Protein Denaturation, Temperature},
	issn = {0009-9147},
	author = {PetitClerc, C}
}
@article {1172196,
	title = {Reduction of enamel solubility by sodium monophosphate},
	journal = {J Dent Res},
	volume = {55},
	number = {3},
	year = {1976},
	month = {1976 May-Jun},
	pages = {510-4},
	abstract = {The preponderance of evidence indicates that sodium monofluorophosphate exerts a highly beneficial effect on dental caries incidence and enamel solubility. Optimal effects are obtained with a concentration of 4 X 10(3) ppm fluoride, by a four-minute application and by adjusting the pH to 4.0. The reaction of sodium monofluorophosphate with enamel is not temperature dependent. Sodium monofluorophosphate is significantly more protective than sodium fluoride in aqueous solutions at all equivalent fluoride concentrations and in pastes at concentrations exceeding 8 X 10(3) ppm fluoride.},
	keywords = {Dental Enamel Solubility, Depression, Chemical, Fluorides, Topical, Humans, Hydrogen-Ion Concentration, Phosphates, Sodium, Temperature, Time Factors},
	issn = {0022-0345},
	doi = {10.1177/00220345760550033401},
	author = {Feller, R P and Shannon, I L and Matranga, L F and Osborne, H W and Perez, R S}
}
@article {1172266,
	title = {[Ability of antilymphocyte sera to counteract the allogeneic inhibition of hematopoietic stem cells]},
	journal = {Dokl Akad Nauk SSSR},
	volume = {223},
	number = {5},
	year = {1975},
	month = {1975 Aug 11},
	pages = {1245-7},
	keywords = {Animals, Antilymphocyte Serum, Cell Division, Clone Cells, Graft Rejection, Hematopoietic Stem Cell Transplantation, Hybridization, Genetic, Mice, Mice, Inbred C57BL, Radiation Chimera, Spleen, Transplantation, Homologous},
	issn = {0002-3264},
	author = {Golovistikov, I N}
}
@article {1172121,
	title = {Antidepressant drugs affect dopamine uptake},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {20},
	year = {1975},
	month = {1975 Oct 15},
	pages = {1896-7},
	keywords = {Animals, Antidepressive Agents, Brain, Central Nervous System Stimulants, Depression, Chemical, Dopamine, In Vitro Techniques, Male, Rats},
	issn = {0006-2952},
	author = {Halaris, A E and Belendiuk, K T and Freedman, D X}
}
@article {1172161,
	title = {Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1349-56},
	keywords = {Animals, Cnidaria, Computers, Hemerythrin, Metalloproteins, Models, Molecular, Muscle Proteins, Protein Conformation, Species Specificity},
	issn = {1090-2104},
	author = {Hendrickson, W A and Ward, K B}
}
@article {1172056,
	title = {Beef liver L-Glutamate dehydrogenase mechanism: presteady state study of the catalytic reduction of 2.oxoglutarate by NADPH},
	journal = {Biochem Biophys Res Commun},
	volume = {67},
	number = {4},
	year = {1975},
	month = {1975 Dec 15},
	pages = {1527-36},
	keywords = {Animals, Cattle, Glutamate Dehydrogenase, Ketoglutaric Acids, Kinetics, Liver, NADP, Oxidation-Reduction, Spectrometry, Fluorescence, Spectrophotometry, Ultraviolet},
	issn = {0006-291X},
	author = {Jallon, J M and Risler, Y and Iwatsubo, M}
}
@article {1172081,
	title = {[Biochemical studies on camomile components/III. In vitro studies about the antipeptic activity of (--)-alpha-bisabolol (author{\textquoteright}s transl)]},
	journal = {Arzneimittelforschung},
	volume = {25},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {1352-4},
	abstract = {(--)-alpha-Bisabolol has a primary antipeptic action depending on dosage, which is not caused by an alteration of the pH-value. The proteolytic activity of pepsin is reduced by 50 percent through addition of bisabolol in the ratio of 1/0.5. The antipeptic action of bisabolol only occurs in case of direct contact. In case of a previous contact with the substrate, the inhibiting effect is lost.},
	keywords = {Dose-Response Relationship, Drug, Hemoglobins, Hydrogen-Ion Concentration, In Vitro Techniques, Methods, Pepsin A, Plants, Medicinal, Sesquiterpenes, Spectrophotometry, Ultraviolet, Trichloroacetic Acid, Tyrosine},
	issn = {0004-4172},
	author = {Isaac, O and Thiemer, K}
}
@article {1172251,
	title = {Charge properties of human pituitary and amniotic fluid prolactins},
	journal = {Endocr Res Commun},
	volume = {2},
	number = {6-7},
	year = {1975},
	month = {1975},
	pages = {379-402},
	abstract = {The apparent isoelectric points (pI) in isoelectric focusing (IF) of human pituitary and amniotic fluid prolactin (hPRL), both non-iodinated and iodinated, were determined. Unresolved mixtures of pituitary hPRL isohormones E and F, and of at least five isohormones found in amniotic fluid, and plasma hPRL exhibit an average pI value of 6.5 - 6.7. Transient state pH values observed or previously reported for hPRL components range from pH 5.9 to 6.8 after correction to standard conditions. At pH 8.1, the major isohormone, hPRL-F, carriers a charge of 2.2 net protons per molecule. The net charge differences among isohormones E, F and G are compatible with acquisition or loss of single charged groups per 20,000 molecular weight. This net charge is similar to that of the least prolactin-bioactive major isohormone of human growth hormone (hGH-B), while the hGH with a bioactivity comparable to that of hPRL exhibits a net charge of 3.4 valence units. The "large" isohormones J and H increased net charges, by a factor of 2-3, in direct proportion to their size increments.},
	keywords = {Amniotic Fluid, Female, Humans, Hydrogen-Ion Concentration, Isoelectric Focusing, Lactation, Pituitary Gland, Pregnancy, Prolactin, Radioimmunoassay},
	issn = {0093-6391},
	author = {Rogol, A D and Ben-David, M and Sheats, R and Rodbard, D and Chrambach, A}
}
@article {1172026,
	title = {Comparison between procaine and isocarboxazid metabolism in vitro by a liver microsomal amidase-esterase},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {16},
	year = {1975},
	month = {1975 Aug 15},
	pages = {1517-21},
	keywords = {Amidohydrolases, Animals, Esterases, Hydrogen-Ion Concentration, In Vitro Techniques, Isocarboxazid, Kinetics, Male, Metals, Microsomes, Liver, Phospholipids, Procaine, Proteins, Rats, Subcellular Fractions, Temperature},
	issn = {1873-2968},
	author = {Moroi, K and Sato, T}
}
@article {1172021,
	title = {Coronary vascular and myocardial responses to carotid body stimulation in the dog},
	journal = {Am J Physiol},
	volume = {229},
	number = {3},
	year = {1975},
	month = {1975 Sep},
	pages = {754-60},
	abstract = {Coronary vascular and myocardial responses to selective hypoxic and/or hypercapnic carotid chemoreceptor stimulation were investigated in constantly ventilated, pentobarbital or urethan-chloralose anesthetized dogs. Bilaterally isolated carotid chemoreceptors were perfused with autologous blood of varying O2 and CO2 tensions via an extracorporeal lung circuit. Systemic gas tensions were unchanged. Effects of carotid chemoreceptor stimulation on coronary vascular resistance, left ventricular dP/dt, and strain-gauge arch output were studied at natural coronary blood flow with the chest closed and during constant-flow perfusion of the left common coronary artery with the chest open. Carotid chemoreceptor stimulation slightly increased left ventricular dP/dt and slightly decreased the strain-gauge arch output, while markedly increasing systemic pressure. Coronary blood flow increased; however, coronary vascular resistance wa.as not affected. These studies show that local carotid body stimulation increases coronary blood flow but has little effect on the myocardium. The increase in coronary blood flow results mainly from an increase in systemic arterial pressure. Thus these data provide little evidence for increased sympathetic activity of the heart during local stimulation of the carotid chemoreceptors with hypoxic and hypercapnic blood.},
	keywords = {Animals, Blood Pressure, Carbon Dioxide, Carotid Body, Carotid Sinus, Chemoreceptor Cells, Coronary Circulation, Dogs, Female, Heart, Heart Rate, Hydrogen-Ion Concentration, Male, Oxygen, Perfusion, Pressure, Vagotomy, Vascular Resistance, Ventricular Function},
	issn = {0002-9513},
	author = {Ehrhart, I C and Parker, P E and Weidner, W J and Dabney, J M and Scott, J B and Haddy, F J}
}
@article {1172071,
	title = {Delineation of the intimate details of the backbone conformation of pyridine nucleotide coenzymes in aqueous solution},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1173-9},
	keywords = {Fourier Analysis, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Conformation, NAD, NADP, Structure-Activity Relationship, Temperature},
	issn = {1090-2104},
	author = {Bose, K S and Sarma, R H}
}
@article {1172051,
	title = {Digitoxin metabolism by rat liver microsomes},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {17},
	year = {1975},
	month = {1975 Sep 01},
	pages = {1639-41},
	keywords = {Animals, Chromatography, Thin Layer, Digitoxigenin, Digitoxin, Hydroxylation, In Vitro Techniques, Male, Microsomes, Liver, NADP, Rats, Time Factors},
	issn = {1873-2968},
	author = {Schmoldt, A and Benthe, H F and Haberland, G}
}
@article {1172116,
	title = {Effect of chloroquine on cultured fibroblasts: release of lysosomal hydrolases and inhibition of their uptake},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1338-43},
	keywords = {Biological Transport, Cells, Cultured, Cerebroside-Sulfatase, Chloroquine, Dextrans, Fibroblasts, Glucuronidase, Humans, Leukodystrophy, Metachromatic, Lysosomes, Pinocytosis, Skin, Sulfatases},
	issn = {1090-2104},
	author = {Wiesmann, U N and DiDonato, S and Herschkowitz, N N}
}
@article {1172031,
	title = {Effect of etafenone on total and regional myocardial blood flow},
	journal = {Arzneimittelforschung},
	volume = {25},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {1400-3},
	abstract = {The distribution of blood flow to the subendocardial, medium and subepicardial layers of the left ventricular free wall was studied in anaesthetized dogs under normoxic (A), hypoxic (B) conditions and under pharmacologically induced (etafenone) coronary vasodilation (C). Regional myocardial blood flow was determined by means of the particle distribution method. In normoxia a transmural gradient of flow was observed, with the subendocardial layers receiving a significantly higher flow rate compared with the subepicardial layers. In hypoxia induced vasodilation this transmural gradient of flow was persistent. In contrast a marked redistribution of regional flow was observed under pharmacologically induced vasodilation. The transmural gradient decreased. In contrast to some findings these experiments demonstrate that a considerable vasodilatory capacity exists in all layers of the myocardium and can be utilized by drugs. The differences observed for the intramural distribution pattern of flow under hypoxia and drug induced vasodilation support the hypothesis that this pattern reflects corresponding gradients of regional myocardial metabolism.},
	keywords = {Animals, Blood Pressure, Carbon Dioxide, Cardiac Output, Coronary Circulation, Coronary Vessels, Dogs, Heart Rate, Heart Septum, Heart Ventricles, Hydrogen-Ion Concentration, Hypoxia, Oxygen, Propiophenones, Vasodilator Agents},
	issn = {0004-4172},
	author = {Flohr, H and Breull, W}
}
@article {1172131,
	title = {The effect of host adrenalectomy on the physiology of Trypanosoma rhodesiense},
	journal = {Comp Biochem Physiol A Comp Physiol},
	volume = {52},
	number = {4},
	year = {1975},
	month = {1975 Dec 01},
	pages = {623-6},
	keywords = {Adrenalectomy, Animals, Biological Transport, Active, Glucose, Liver Glycogen, Rats, Trypanosoma},
	issn = {0300-9629},
	author = {Sanchez, G and Alderete, J F}
}
@article {1172276,
	title = {The effect of o-salicylate upon pentose phosphate pathway activity in normal and G6PD-deficient red cells},
	journal = {Br J Haematol},
	volume = {30},
	number = {2},
	year = {1975},
	month = {1975 Jun},
	pages = {225-31},
	abstract = {The effect of the major metabolite of aspirin, namely salicylic acid, upon the pentose phosphate pathway (PPP) of normal and G6PD-deficient red cells has been studied. Salicylic acid was shown to inhibit this pathway in proportion to the amount present. At any concentration of this substance there was greater inhibition of the PPP in G6PD-deficient than in normal red cells.},
	keywords = {Blood Glucose, Erythrocytes, Glucosephosphate Dehydrogenase Deficiency, Humans, Hydrogen-Ion Concentration, Methylene Blue, Pentosephosphates, Sodium Salicylate},
	issn = {0007-1048},
	author = {Worathumrong, N and Grimes, A J}
}
@article {1172141,
	title = {Effects of 5,6-dihydroxytryptamine on tyrosine-hydroxylase activity in central catecholaminergic neurons of the rat},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1739-42},
	keywords = {5,6-Dihydroxytryptamine, Animals, Brain, Catecholamines, Cerebral Cortex, Cisterna Magna, Corpus Striatum, In Vitro Techniques, Injections, Male, Neurons, Rats, Rats, Inbred Strains, Stimulation, Chemical, Substantia Nigra, Time Factors, Tryptamines, Tyrosine 3-Monooxygenase},
	issn = {0006-2952},
	author = {Renaud, B and Buda, M and Lewis, B D and Pujol, J F}
}
@article {1172181,
	title = {[Electrocardiographic examinations of the rural population of Kirghizia]},
	journal = {Zdravookhr Kirg},
	number = {3},
	year = {1975},
	month = {1975 May-Jun},
	pages = {25-7},
	keywords = {Adult, Age Factors, Aged, Electrocardiography, Female, Heart, Humans, Kyrgyzstan, Male, Middle Aged, Rural Health},
	issn = {0132-8867},
	author = {Sydygaliev, K S}
}
@article {1172291,
	title = {[Expediency of including ganglionic blockaders and neuroleptics in the complex treatment of vibration disease]},
	journal = {Vrach Delo},
	number = {7},
	year = {1975},
	month = {1975 Jul},
	pages = {132-5},
	keywords = {Follow-Up Studies, Ganglionic Blockers, Humans, Occupational Diseases, Tranquilizing Agents, Vibration},
	issn = {0049-6804},
	author = {Bel{\textquoteright}skaia, M L and Turutina, A P}
}
@article {1172016,
	title = {Formate assay in body fluids: application in methanol poisoning},
	journal = {Biochem Med},
	volume = {13},
	number = {2},
	year = {1975},
	month = {1975 Jun},
	pages = {117-26},
	keywords = {Aldehyde Oxidoreductases, Animals, Body Fluids, Carbon Dioxide, Formates, Haplorhini, Humans, Hydrogen-Ion Concentration, Kinetics, Methanol, Methods, Pseudomonas},
	issn = {0006-2944},
	author = {Makar, A B and McMartin, K E and Palese, M and Tephly, T R}
}
@article {1172046,
	title = {A heparan sulfate-degrading endoglycosidase from rat liver tissue},
	journal = {Biochem Biophys Res Commun},
	volume = {67},
	number = {4},
	year = {1975},
	month = {1975 Dec 15},
	pages = {1422-8},
	keywords = {Animals, Cell Line, Glycosaminoglycans, Glycoside Hydrolases, Heparitin Sulfate, Hydrogen-Ion Concentration, Liver, Lysosomes, Male, Rats},
	issn = {0006-291X},
	author = {H{\"o}{\"o}k, M and Wasteson, A and Oldberg, A}
}
@article {1172231,
	title = {Identification of NADPH-thioredoxin reductase system in Euglena gracillis},
	journal = {Proc Natl Acad Sci U S A},
	volume = {72},
	number = {11},
	year = {1975},
	month = {1975 Nov},
	pages = {4233-7},
	abstract = {Euglena gracilis contains a protein system which can utilize the reducing power of NADPH in the ribonucleotide reductase-catalyzed reduction of CTP. The proteins required for this reaction are a flavoprotien with a molecular weight of approximately 185,000 which is functionally similar to thioredoxin reductase (NADPH), EC 1.6.4.5, and another protein (Protein I) whose function in the reaction is unknown. This new protein does not appear to contain a prosthetic group and has a molecular weight of approximately 240,000. In addition, the ribonucleotide reductase active in the Euglena NADPH-thioredoxin reductase system is more complex than the protein reported in a previous publication [(1974) j. Biol. Chem. 249, 4428-4434]. The enzyme preparation described in this report contains four different types of polypeptide chains which may complex to form the active enzyme.},
	keywords = {Cytosine Nucleotides, Euglena gracilis, Molecular Weight, NADH, NADPH Oxidoreductases, NADP, Protein Conformation, Ribonucleotide Reductases, Thioredoxin-Disulfide Reductase},
	issn = {0027-8424},
	author = {Munavalli, S and Parker, D V and Hamilton, F D}
}
@article {1172061,
	title = {Improvement of sperm motility in patients with asthenozoospermia by kallikrein treatment},
	journal = {Int J Fertil},
	volume = {20},
	number = {1},
	year = {1975},
	month = {1975},
	pages = {61-3},
	abstract = {Parenteral and oral application of kallikrein (EC 3.4.21.8)--a kinin-releasing proteinase from porcine pancreatic tissue--significantly stimulates quantitative and qualitative sperm motility in subfertile males with semen criteria of asthenozoospermia. Improvement of sperm motility was found to exist for at least 3 months following termination of the 7 week duration kallikrein treatment. Additionally, a significant increase in the number of spermatozoa was observed 3 and 5 months after starting parenteral application of kallikrein.},
	keywords = {Administration, Oral, Humans, Infertility, Male, Injections, Kallikreins, Male, Sperm Motility, Stimulation, Chemical},
	issn = {0020-725X},
	author = {Schill, W B}
}
@article {1172166,
	title = {Increase in acetyl CoA synthetase activity after phenobarbital treatment},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1725-7},
	keywords = {Acetate-CoA Ligase, Acetylesterase, Acetylglucosamine, Animals, Coenzyme A Ligases, Cycloheximide, Glucosamine, Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing), Liver, Male, Phenobarbital, Phosphotransferases, Proteins, Rats, Stimulation, Chemical},
	issn = {0006-2952},
	author = {Akamatsu, N and Nakajima, H and Ono, M and Miura, Y}
}
@article {1172201,
	title = {Inhibition of aldehyde reductase by acidic metabolites of the biogenic amines},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1731-3},
	keywords = {Aldehyde Oxidoreductases, Animals, Biogenic Amines, Brain, Homovanillic Acid, In Vitro Techniques, Kinetics, NADP, Pyrimidines, Sheep},
	issn = {0006-2952},
	author = {Turner, A J and Hick, P E}
}
@article {1172076,
	title = {The interaction of phospholipase A2 with micellar interfaces. The role of the N-terminal region},
	journal = {Biochemistry},
	volume = {14},
	number = {25},
	year = {1975},
	month = {1975 Dec 16},
	pages = {5387-94},
	abstract = {The localization of the previously postulated interface recognition site (IRS) in porcine pancreatic phospholipase A2, required for a specific interaction between the enzyme and organized lipid-water interfaces, was investigated by ultraviolet difference spectroscopy, by measurements of the intrinsic fluorescence of the unique Trp residue, and by protection experiments against specific tryptic hydrolysis. Using the enzymically nondegradable substrate analogues: CnH(2n+1)(0-)OOCH2CH2N+(CH3)3-(H,OH), it is shown that the rather hydrophobic N-terminal sequence of the enzyme, viz., Ala-Leu-Trp-Gln-Phe-Arg, is directly involved in the interaction with the lipid-water interface. Besides hydrophobic probably also polar interactions contribute to the binding process. At neutral or acidic pH the presence of a salt bridge between the N-terminal alpha-NH3+ group and a negatively charged side chain stablizes the interface recognition site and allows the enzyme to penetrate micellar surfaces, even in the absence of metal ion. At alkaline pH, interaction of the enzyme with micellar interfaces requires the presence of Ca2+ (Ba2+) ions.},
	keywords = {Amines, Barium, Binding Sites, Calcium, Hydrogen-Ion Concentration, Kinetics, Lysophosphatidylcholines, Micelles, Pancreas, Phosphatidylcholines, Phospholipases, Protein Conformation, Trypsin},
	issn = {0006-2960},
	author = {van Dam-Mieras, M C and Slotboom, A J and Pieterson, W A and de Haas, G H}
}
@article {1172171,
	title = {Kinetic studies and effects of anions on creatine phosphokinase from skeletal muscle of rhesus monkey (Macaca mulatta)},
	journal = {Biochim Biophys Acta},
	volume = {410},
	number = {1},
	year = {1975},
	month = {1975 Nov 20},
	pages = {99-114},
	abstract = {A purification procedure for creatine kinase (EC 2.7.3.2) from muscle of the monke35--170 muequiv H+/mg protein per min at 30 degrees C and a yield of approx. 0.5 g/kg muscle. Assuming equilibrium kinetics, synergistic binding of substrates at one catalytic site is found for both the forward and back reactions. Kinetic constants for the binding of each substrate to the free enzyme and the enzyme-second substrate complex are determined and are compared with those for the enzyme from other species. Inhibition by small anions is determined in the presence of different combinations of substrates and products. SO4(2-) inhibits by simple competitive inhibition and probably binds at the site of the transferrable phosphoryl group. Inhibition by NO3-, NO2-, SCN- and Cl- is more complex and these ions are suggested to mimic the transferrable phosphoryl group in a planar transition-state complex. These anions stabilize the dead-end complex, enzyme-creatine-MgADP, which lacks the transferable phosphoryl group. The effects of these anions on the dissociation constants of the enzyme-substrate complexes is reported and is in accord with the above hypothesis. The dead-end complex in the absence of anion does not protect the essential thiol group against inhibition by iodoacetamide. Addition of NO3- or Cl- to the dead-end complex or a substrate equilibrium mixture without anion confers protection. The essential thiol group is inhibited by iodoacetamide at a rate which is essentially independent of pH over the normal stability range of the enzyme. Contrary to our previous report this pH independence is not altered by the presence of dead-end complex, creatine plus MgADP, in the presence or absence of anion or in the presence of a substrate equilibrium mixture. It is inferred that the {\textquoteright}essential{\textquoteright} thiol group of the monkey enzyme has essentially the same properties as that of the rabbit enzyme. In consequence, the inferences made about the role of this group based on our previous work on the monkey enzyme are no longer valid. The present findings are compatible with the essential thiol group playing a conformational role in the catalytic process.},
	keywords = {Acetates, Adenosine Triphosphate, Animals, Anions, Creatine Kinase, Enzyme Activation, Haplorhini, Hydrogen-Ion Concentration, Iodoacetamide, Kinetics, Macaca mulatta, Magnesium, Muscles, Organ Specificity, Rabbits, Species Specificity},
	issn = {0006-3002},
	author = {Chegwidden, W R and Watts, D C}
}
@article {1172211,
	title = {Lysosomal hydrolases of the epidermis. 2. Ester hydrolases},
	journal = {Br J Dermatol},
	volume = {93},
	number = {4},
	year = {1975},
	month = {1975 Oct},
	pages = {391-8},
	abstract = {Five distinct ester hydrolases (EC 3-1) have been characterized in guinea-pig epidermis. These are carboxylic esterase, acid phosphatase, pyrophosphatase, and arylsulphatase A and B. Their properties are consistent with those of lysosomal enzymes.},
	keywords = {Acid Phosphatase, Animals, Carboxylic Ester Hydrolases, Cerebroside-Sulfatase, Chondro-4-Sulfatase, Guinea Pigs, Hydrogen-Ion Concentration, Hydrolases, Kinetics, Lysosomes, Pyrophosphatases, Skin},
	issn = {0007-0963},
	author = {Mier, P D and van den Hurk, J J}
}
@article {1172176,
	title = {Malathion A and B esterases of mouse liver-I},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {18},
	year = {1975},
	month = {1975 Sep 15},
	pages = {1713-7},
	keywords = {Animals, Drug Stability, Esterases, Female, Hydrogen-Ion Concentration, Liver, Malathion, Male, Metals, Mice, Sex Factors, Sulfhydryl Compounds},
	issn = {0006-2952},
	author = {Bhagwat, V M and Ramachandran, B V}
}
@article {1172101,
	title = {Maturation of the adrenal medulla--IV. Effects of morphine},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {16},
	year = {1975},
	month = {1975 Aug 15},
	pages = {1469-74},
	keywords = {Adrenal Medulla, Aging, Animals, Animals, Newborn, Body Weight, Catecholamines, Dopamine beta-Hydroxylase, Epinephrine, Female, Humans, In Vitro Techniques, Maternal-Fetal Exchange, Metaraminol, Morphine, Morphine Dependence, Pregnancy, Rats, Tyrosine 3-Monooxygenase},
	issn = {1873-2968},
	author = {Randerson, James, T and Slotkin, T A}
}
@article {1172096,
	title = {Metal substitutions incarbonic anhydrase: a halide ion probe study},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1281-6},
	keywords = {Animals, Binding Sites, Cadmium, Carbonic Anhydrases, Cattle, Humans, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Mercury, Protein Binding, Protein Conformation, Zinc},
	issn = {0006-291X},
	author = {Smith, R J and Bryant, R G}
}
@article {1172041,
	title = {Modification of human erythrocyte ghosts with transglutaminase},
	journal = {Biochem Biophys Res Commun},
	volume = {67},
	number = {3},
	year = {1975},
	month = {1975 Dec 01},
	pages = {1158-66},
	keywords = {Animals, Blood Proteins, Cadaverine, Cell Membrane, Dansyl Compounds, Erythrocytes, gamma-Glutamyltransferase, Guinea Pigs, Humans, Liver, Molecular Weight, Putrescine},
	issn = {0006-291X},
	author = {Lorand, L and Shishido, R and Parameswaran, K N and Steck, T L}
}
@article {1172286,
	title = {New health practitioner education: problems and issues},
	journal = {J Med Educ},
	volume = {50},
	number = {12 pt 2},
	year = {1975},
	month = {1975 Dec},
	pages = {67-73},
	keywords = {Accreditation, Costs and Cost Analysis, Health Expenditures, Interprofessional Relations, Nurse Practitioners, Patient Care Team, Physician Assistants, Primary Health Care, Quality of Health Care, United States},
	issn = {0022-2577},
	author = {Sadler, A M}
}
@article {1172186,
	title = {[Organization of medical aid to patients with mandibular fractures in the Kirghiz SSR]},
	journal = {Zdravookhr Kirg},
	number = {3},
	year = {1975},
	month = {1975 May-Jun},
	pages = {7-9},
	keywords = {Hospital Administration, Humans, Kyrgyzstan, Mandibular Fractures, Outpatient Clinics, Hospital},
	issn = {0132-8867},
	author = {Mamytov, A M}
}
@article {1172126,
	title = {The oxygen affinity of haemoglobin Tak, a variant with an elongated beta chain},
	journal = {Biochim Biophys Acta},
	volume = {412},
	number = {2},
	year = {1975},
	month = {1975 Dec 15},
	pages = {288-94},
	abstract = {The oxygen affinity was investigated of purified Hb Tak, a human haemoglobin variant with elongated beta-chains. A very low P50 value was found which was not influenced by the addition of 2,3 diphosphoglycerate. The n value was 1, indicating non-cooperativity. The oxygen equilibrium curve of the whole blood haemolysate containing Hbs A and Tak was close to that of Hb A at the top of the curve, while the bottom of the curve greatly deviated from the latter, indicative of small if any interaction between Hb A and Tak during oxygenation.},
	keywords = {Diphosphoglyceric Acids, Genetic Variation, Hemoglobins, Abnormal, Humans, Hydrogen-Ion Concentration, Oxygen, Peptide Fragments, Phytic Acid, Protein Binding},
	issn = {0006-3002},
	author = {Imai, K and Lehmann, H}
}
@article {1172086,
	title = {Purification of an immunosuppressive principle from Ehrlich carcinoma ascites},
	journal = {Gan},
	volume = {66},
	number = {5},
	year = {1975},
	month = {1975 Oct},
	pages = {569-72},
	abstract = {An immunosuppressive factor was purified from Ehrlich carcinoma ascites by the combination of ultrafiltration and Sephadex chromatography. The resulting product showed 50\% reduction in the number of splenic plaque-forming cells in mice immunized with sheep red blood cells when as low as 50 mug dose was given twice intraperitoneally before erythrocyte injection. The molecular size of the product was between 30,000 and 100,000, and it was relatively heat unstable.},
	keywords = {Animals, Carcinoma, Ehrlich Tumor, Dose-Response Relationship, Drug, Female, Hemolytic Plaque Technique, Hydrogen-Ion Concentration, Immunosuppressive Agents, Male, Mice, Molecular Weight},
	issn = {0016-450X},
	author = {Motoki, H and Kurokawa, T and Shiraishi, H and Kitame, F and Ono, Y}
}
@article {1172236,
	title = {[Quantitative colorimetric determination of 1-(4-cyclohexylureidophenoxy)-2-hydroxy-3-tert butylaminopropane (talinolol Cordanum, 02-115) in body fluids]},
	journal = {Pharmazie},
	volume = {30},
	number = {10},
	year = {1975},
	month = {1975 Oct},
	pages = {673},
	keywords = {Adrenergic beta-Antagonists, Animals, Body Fluids, Colorimetry, Hydrolysis, Propanolamines},
	issn = {0031-7144},
	author = {N{\"u}rnberger, H}
}
@article {1172036,
	title = {Radiochemical assay of glutathione S-epoxide transferase and its enhancement by phenobarbital in rat liver in vivo},
	journal = {Biochem Pharmacol},
	volume = {24},
	number = {17},
	year = {1975},
	month = {1975 Sep 01},
	pages = {1569-72},
	keywords = {Animals, Carrier Proteins, Epoxy Compounds, Glutathione, Glutathione Transferase, Hydrogen-Ion Concentration, Liver, Male, Methylcholanthrene, Phenobarbital, Rats, Stimulation, Chemical, Styrenes},
	issn = {0006-2952},
	author = {Marniemi, J and Parkki, M G}
}
@article {1172281,
	title = {The regional workshops on primary care},
	journal = {J Med Educ},
	volume = {50},
	number = {12 pt 2},
	year = {1975},
	month = {1975 Dec},
	pages = {201-9},
	keywords = {Community Participation, Congresses as Topic, Education, Medical, Evaluation Studies as Topic, Financing, Organized, Group Processes, Organization and Administration, Primary Health Care, United States},
	issn = {0022-2577},
	author = {Nourse, E S}
}
@article {1172106,
	title = {Response to exogenous gonadotropins in the unresponsive ovary syndrome},
	journal = {Int J Gynaecol Obstet},
	volume = {13},
	number = {1},
	year = {1975},
	month = {1975},
	pages = {23-8},
	keywords = {17-Ketosteroids, Adult, Amenorrhea, Body Temperature, Chorionic Gonadotropin, Estrogens, Female, Follicle Stimulating Hormone, Humans, Menotropins, Ovary, Pregnanediol},
	issn = {0020-7292},
	author = {Zourlas, P A}
}
@article {1172226,
	title = {Studies of oxygen binding energy to hemoglobin molecule},
	journal = {Biochem Biophys Res Commun},
	volume = {66},
	number = {4},
	year = {1975},
	month = {1975 Oct 27},
	pages = {1424-31},
	keywords = {Binding Sites, Cobalt, Hemoglobins, Humans, Hydrogen-Ion Concentration, Iron, Ligands, Mathematics, Oxygen, Oxyhemoglobins, Protein Binding, Spectrum Analysis},
	issn = {0006-291X},
	author = {Chow, Y W and Pietranico, R and Mukerji, A}
}
@article {1172261,
	title = {[Studies on the action of an anticholinergic agent in combination with a tranquilizer on gastric juice secretion in man]},
	journal = {Arzneimittelforschung},
	volume = {25},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {1460-3},
	abstract = {A double-blind study with intra-individual comparisons was carried out to investigate the effects of 15 mg of (8r)-3alpha-hydroxy-8-isopropyl-1alphaH-tropanium bromide(+/-)-tropate (Sch 1000), 15 mg Sch 1000 + 10 mg oxazepam, 10 mg oxazepam and placebo with oral administration in randomized sequence on gastric juice volume, amount of acid, concentration and pH values in 12 healthy volunteers. The secretion parameters were measured during a 1-h basal period and a 2-h stimulation period. The gastric juice was obtained in 15 min portions via stomach tube. Stimulation was effected by 1 mug/kg/h pentagastrin via drip infusion. The Friedman test was used for the comparative statistical evaluation, and individual comparisons were carried out by means of the Wilcoxon test (pair-differences rank). The results show that Sch 1000 and Sch 1000 + oxazepam were equal in effect on basal and stimulated secretion volume. As compared with placebo, it was not possible to establish an effect on secretion volume for oxazepam alone. Sch 1000 and Sch 1000 + oxazepam were found to be equipotent in reducing the amount of basal acid, while oxazepam reduced this quantity only during the first 30 min of basal secretion. None of the three active preparations was capable of inhibiting the stimulated acid, although both Sch 1000 preparations produced a clear trend towards lowered mean values. During the basal secretion period, all three test preparations had an inhibiting action on acid concentration, but none of them had a significant effect during the stimulation period. The pH value was savely increased only by Sch 1000 and Sch 1000 + oxazepam, and this even only during the basal period. The results are discussed.},
	keywords = {Adult, Atropine Derivatives, Clinical Trials as Topic, Depression, Chemical, Drug Combinations, Female, Gastric Juice, Humans, Hydrogen-Ion Concentration, Ipratropium, Male, Middle Aged, Oxazepam, Pentagastrin, Time Factors},
	issn = {0004-4172},
	author = {Scherberger, R R and Kaess, H and Br{\"u}ckner, S}
}
@article {1172241,
	title = {Subtilopeptidase A isoenzyme system. Interaction with serum components and its importance for quantitative immunoelectrophoresis},
	journal = {Biochem J},
	volume = {151},
	number = {1},
	year = {1975},
	month = {1975 Oct},
	pages = {149-55},
	abstract = {A method was developed which involved electroimmunoassay and crossed immunoelectrophoresis of subtilopeptidase A (EC 3.4.21.14). Initial trials with unfractionated antiserum were not successful and interaction of the enzyme with non-immunoglobulin serum components were shown to be the cause of the failures. Quantitative immunoelectrophoresis was possible when purified immunoglobulins were used. A pH of 6.5 (lower than the usual pH 8.6) was necessary to obtain a proper baseline definition. Subtilopeptidase A was confirmed as a multiple isoenzyme system. Qualitative inter-batch variations were detected. Di-isopropyl phosphorofluoridate inhibition altered the electrophoretic pattern, but no loss of antigenic determinants was observed.},
	keywords = {Animals, Humans, Hydrogen-Ion Concentration, Immunoassay, Immunoelectrophoresis, Two-Dimensional, Immunoglobulins, Isoenzymes, Isoflurophate, Rabbits, Subtilisins},
	issn = {0264-6021},
	author = {Verbruggen, R}
}
@article {1172146,
	title = {[Sympathico-adrenal system activity in a primary immune response]},
	journal = {Zh Mikrobiol Epidemiol Immunobiol},
	number = {9},
	year = {1975},
	month = {1975 Sep},
	pages = {88-92},
	abstract = {Experiments were carried out on linear mice immunized with sheep erythrocytes; it was found that the primary immune respose developed against the background of significant changes in the state of the sympathico-adrenal system, whose activity was determined by the dynamics of catecholamines in the blood and in the tissues of a number of organs, including the thymus, the spleen and the lymph nodes. By comparing the value of specific and neurohumoral indices it was revealed that the neurohumoral shifts preceded the maximal development of the immune response. On the example of studying the catecholamine dynamics the opinion on a close association between the state of the regulatory mechanisms and the effector formations responsible for the formation of specific immunological reactions was confirmed. It is suggested that a full-value immunological response developed on condition of activation of the sympathico-adrenal system.},
	keywords = {Adrenal Glands, Animals, Antibody-Producing Cells, Cell Count, Epinephrine, Hemagglutinins, Immunity, Immunization, Lymphoid Tissue, Male, Neurotransmitter Agents, Norepinephrine, Rats, Rats, Inbred Strains, Spleen, Sympathetic Nervous System, Time Factors},
	issn = {0372-9311},
	author = {Vasina, I G and Frolov, E P and Serebriakov, N G}
}
@article {1172221,
	title = {Alpha-1-antitrypsin deficiency},
	journal = {S Afr Med J},
	volume = {45},
	number = {6},
	year = {1971},
	month = {1971 Feb 06},
	pages = {144-6},
	keywords = {Adult, Blood Protein Electrophoresis, Genotype, Homozygote, Humans, Lung Diseases, Male, Metabolism, Inborn Errors, Respiratory Function Tests, Trypsin Inhibitors},
	issn = {0256-9574},
	author = {Kanarek, D J and Zwi, S and Milne, F J and Goldman, H I}
}
@article {1172156,
	title = {The sulphonamides in the management of disease of the gut},
	journal = {Practitioner},
	volume = {206},
	number = {231},
	year = {1971},
	month = {1971 Jan},
	pages = {12-5},
	keywords = {Cholera, Colitis, Ulcerative, Crohn Disease, Dysentery, Bacillary, Gastrointestinal Diseases, Humans, Sprue, Tropical, Sulfonamides},
	issn = {0032-6518},
	author = {Badenoch, J}
}
