Cell
Volume 184, Issue 1, 7 January 2021, Pages 226-242.e21
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Article
Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy

https://doi.org/10.1016/j.cell.2020.11.018Get rights and content
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Highlights

  • CRC cells possess an equipotent capacity to enter a drug-tolerant persister state

  • Tumors that recur following a DTP state maintain clonal complexity

  • DTP-state tumors are similar to diapause, an embryonic survival program

  • Similar to diapause, DTPs are dependent on autophagy for survival

Summary

Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.

Keywords

colorectal cancer
chemotherapy
barcode
drug tolerant persisters
equipotent
diapause
slow-cycling
MRD
autophagy
mTOR

Cited by (0)

15

These authors contributed equally

16

Present address: Department of Clinical and Translational Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA

17

Lead Contact