An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

Eugen Dhimolea; Ricardo de Matos Simoes; Dhvanir Kansara; Aziz Al'Khafaji; Juliette Bouyssou; Xiang Weng; Shruti Sharma; Joseline Raja; Pallavi Awate; Ryosuke Shirasaki; Huihui Tang; Brian J Glassner; Zhiyi Liu; Dong Gao; Jordan Bryan; Samantha Bender; Jennifer Roth; Michal Scheffer; Rinath Jeselsohn; Nathanael S Gray; Irene Georgakoudi; Francisca Vazquez; Aviad Tsherniak; Yu Chen; Alana Welm; Cihangir Duy; Ari Melnick; Boris Bartholdy; Myles Brown; Aedin C Culhane; Constantine S Mitsiades

doi:10.1016/j.ccell.2020.12.002

An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

Cancer Cell. 2021 Feb 8;39(2):240-256.e11. doi: 10.1016/j.ccell.2020.12.002. Epub 2021 Jan 7.

Authors

Eugen Dhimolea¹, Ricardo de Matos Simoes², Dhvanir Kansara³, Aziz Al'Khafaji⁴, Juliette Bouyssou⁵, Xiang Weng⁶, Shruti Sharma⁶, Joseline Raja⁶, Pallavi Awate⁶, Ryosuke Shirasaki², Huihui Tang², Brian J Glassner², Zhiyi Liu⁷, Dong Gao⁸, Jordan Bryan⁴, Samantha Bender⁴, Jennifer Roth⁴, Michal Scheffer², Rinath Jeselsohn⁹, Nathanael S Gray⁹, Irene Georgakoudi⁷, Francisca Vazquez⁴, Aviad Tsherniak⁴, Yu Chen⁸, Alana Welm¹⁰, Cihangir Duy¹¹, Ari Melnick¹², Boris Bartholdy¹³, Myles Brown⁹, Aedin C Culhane¹⁴, Constantine S Mitsiades¹⁵

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA. Electronic address: eugen_dhimolea@dfci.harvard.edu.
² Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Ludwig Center at Harvard, Boston, MA, USA.
⁴ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA.
⁷ Department of Biomedical Engineering, Tufts University, Medford, MA, USA.
⁸ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
¹⁰ Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
¹¹ Department of Medicine, Weill Cornell Medicine, New York, NY, USA; Cancer Signaling and Epigenetics Program, Institute for Cancer Research, Cancer Epigenetics Institute, Fox Chase Cancer Center, Philadelphia, PA, USA.
¹² Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
¹³ Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹⁴ Department of Data Sciences, Dana-Farber Cancer Institute & Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ludwig Center at Harvard, Boston, MA, USA. Electronic address: constantine_mitsiades@dfci.harvard.edu.

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: CDK9; CRISPR; MYC; adaptation to stress; breast cancer; cancer; diapause; drug persistence; prostate cancer; residual tumor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adaptation, Physiological / drug effects
Adaptation, Physiological / genetics*
Animals
Antineoplastic Agents / pharmacology
Apoptosis / genetics
Cell Line
Cell Line, Tumor
Cyclin-Dependent Kinase 9 / genetics
Diapause / drug effects
Diapause / genetics
Embryo, Mammalian / drug effects
Embryo, Mammalian / physiology*
Female
HEK293 Cells
Humans
MCF-7 Cells
Mice
Proto-Oncogene Proteins c-myc / genetics*
Transcription Factors / genetics
Transcription, Genetic / genetics
Up-Regulation / drug effects
Up-Regulation / genetics

Substances

Antineoplastic Agents
Proto-Oncogene Proteins c-myc
Transcription Factors
Cyclin-Dependent Kinase 9

Abstract

Publication types

MeSH terms

Substances

Grants and funding