An embryonic diapause-like adaptation with suppressed Myc activity enables tumor treatment persistence Journal Article

   

Authors:	Dhimolea, E.; de Matos Simoes, R.; Kansara, D.; Al'Khafaji, A.; Bouyssou, J.; Weng, X.; Sharma, S.; Raja, J.; Awate, P.; Shirasaki, R.; Tang, H.; Glassner, B. J.; Liu, Z.; Gao, D.; Bryan, J.; Bender, S.; Roth, J.; Scheffer, M.; Jeselsohn, R.; Gray, N. S.; Georgakoudi, I.; Vazquez, F.; Tsherniak, A.; Chen, Y.; Welm, A.; Duy, C.; Melnick, A.; Bartholdy, B.; Brown, M.; Culhane, A. C.; Mitsiades, C. S.
Article 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. © 2020 Elsevier Inc. Dhimolea et al. document that cancer cell persistence during cytotoxic treatment is enabled by Myc inactivation and a biosynthetically paused adaptation resembling embryonic diapause. Myc-suppressed cancer cells have low redox stress and attenuated apoptotic priming. Interfering with this adaptive response of chemo-persistent cells enhances their chemosensitivity. © 2020 Elsevier Inc.
Keywords:	breast cancer; prostate cancer; myc; cancer; cdk9; crispr; residual tumor; diapause; adaptation to stress; drug persistence
Journal Title:	Cancer Cell
Volume:	39
Issue:	2
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2021-02-08
Start Page:	240
End Page:	256.e11
Language:	English
DOI:	10.1016/j.ccell.2020.12.002
PUBMED:	33417832
PROVIDER:	scopus
PMCID:	PMC8670073
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099703860&doi=10.1016%2fj.ccell.2020.12.002&partnerID=40&md5=42ef8f1fcbc56f4bcd027e1082ac36af
Notes:	Article -- Export Date: 1 March 2021 -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/177536