Journal
CELL
Volume 184, Issue 1, Pages 226-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.11.018
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Funding
- Canadian Institutes of Health Research [FDN-148479, MOP-142375, 420231]
- Terry Fox Foundation [TFRI-1029]
- Canada 150 Research Chair in Developmental Epigenetics
- NSERC Discovery Grants Program [RGPIN 1505]
- Canada Research Chair in Translational Colorectal Cancer Research
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It has been discovered that cancer cells enter a drug-tolerant persister state to evade treatment, showing similarities with diapause in embryonic development. All cancer cells possess the potential to become drug-tolerant persisters, rather than just a small subpopulation.
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.
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