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. GrayIrene Georgakoudi, Francisca Vazquez, Aviad Tsherniak, Yu Chen, Alana Welm, Cihangir Duy, Ari Melnick, Boris Bartholdy, Myles Brown, Aedin C. Culhane, Constantine S. Mitsiades

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)240-256.e11
JournalCancer Cell
Volume39
Issue number2
DOIs
StatePublished - Feb 8 2021

Keywords

  • CDK9
  • CRISPR
  • MYC
  • adaptation to stress
  • breast cancer
  • cancer
  • diapause
  • drug persistence
  • prostate cancer
  • residual tumor

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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