@article{6a3041b1fd334db9be8ef836f4143d6e,
title = "An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence",
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",
author = "Eugen Dhimolea and {de Matos Simoes}, Ricardo and Dhvanir Kansara and Aziz Al'Khafaji and Juliette Bouyssou and Xiang Weng and Shruti Sharma and Joseline Raja and Pallavi Awate and Ryosuke Shirasaki and Huihui Tang and Glassner, {Brian J.} and Zhiyi Liu and Dong Gao and Jordan Bryan and Samantha Bender and Jennifer Roth and Michal Scheffer and Rinath Jeselsohn and Gray, {Nathanael S.} and Irene Georgakoudi and Francisca Vazquez and Aviad Tsherniak and Yu Chen and Alana Welm and Cihangir Duy and Ari Melnick and Boris Bartholdy and Myles Brown and Culhane, {Aedin C.} and Mitsiades, {Constantine S.}",
note = "Funding Information: We thank Nicholas Navin, Ruli Gao (UT MD Anderson Cancer Center), Theodoros Foukakis (Karolinska Institutet), and Ingrid Hedenfalk (Lund University Cancer Center) for providing information about the patient molecular data. We thank Keith Blackwell (Joslin Diabetes Center), Andrew Kung (MSKCC), Todd Golub (Broad Institute), William Hahn (DFCI/Broad Institute), Ana Soto and Carlos Sonnenschein (Tufts University), Toshihiro Shioda (MGH), Bruce Zetter (Boston Children's Hospital), and William Kaelin (DFCI) for useful discussions and advice. We also thank Megan Bariteau and Jeffrey Sorrell for administrative and organizational support of the study. Funding for this work was from the Breast Cancer Alliance Young Investigator Award (E.D. C.S.M.), the Claudia Adams Barr Program for Innovative Cancer Research (E.D. M.S. C.S.M.), the Hellenic Women's Club (C.S.M. E.D.), a Terri Brodeur Breast Cancer Foundation grant (E.D.), the Avon Foundation Breast Cancer Research Program (C.S.M. E.D.), an Elsa U. Pardee Foundation grant (C.S.M. E.D.), Department of Defense grant W81XWH-15-1-0012 (A.C.C. C.S.M.), the Ludwig Center at Harvard (C.S.M.), the Leukemia and Lymphoma Society Scholar Award (C.S.M.), and NIH R01 grant CA179483 (C.S.M. N.S.G.). Processing of raw CRISPR and RNA-sequencing data was performed on the Orchestra High-Performance Compute Cluster at Harvard Medical School (grant NCRR 1S10RR028832-01, http://rc.hms.harvard.edu). E.D. and C.S.M. conceived the project. E.D. designed and executed or supervised the execution of the experiments and analyzed the data. R.d.M.S. A.C.C. and B.B. performed bioinformatic analyses and visualization. D.K. S.S. X.W. P.A. J.B. J.R. H.T. Z.L. L.W. S.B. B.G. J.B. Z.L. M.S. and R.S. performed experiments or assisted in their execution. A.A.K. N.S.G. F.V. R.J. A.T. I.G. J.R. Y.C. D.G. A.W. C.D. A.M. and M.B. provided models or input with data analysis and interpretation. E.D. and C.S.M. wrote the manuscript with input from the co-authors. E.D. and C.S.M. are co-inventors on a patent related to the use of 3D cultures. Y.C. reports personal fees from Oric Pharmaceuticals outside the submitted work. R.J. reports research funding from Pfizer and Lilly and consulting for Carrick and Luminex. M.B. reports sponsored research support from Novartis; serves on the science advisory board (SAB) of and received fees from Kronos Bio, GV20 Oncotherapy, and H3 Biomedicine; and holds equity in Kronos Bio and GV20 Oncotherapy. N.S.G. is a founder, SAB member, and equity holder in Gatekeeper, Syros, Petra, C4, Allorion, Jengu, Inception, B2S, and Soltego (board member) and his lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Her2llc, Deerfield, and Sanofi. C.S.M. discloses research funding from Janssen/Johnson & Johnson, Teva, EMD Serono, Abbvie, Arch Oncology, Karyopharm, Sanofi, and Nurix; employment of a relative with Takeda; and consultant/honoraria from Fate Therapeutics, Ionis Pharmaceuticals, and FIMECS. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = feb,
day = "8",
doi = "10.1016/j.ccell.2020.12.002",
language = "English (US)",
volume = "39",
pages = "240--256.e11",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "2",
}
