| Literature DB >> 33417860 |
Sumaiyah K Rehman1, Jennifer Haynes1, Evelyne Collignon2, Kevin R Brown3, Yadong Wang1, Allison M L Nixon4, Jeffrey P Bruce1, Jeffrey A Wintersinger5, Arvind Singh Mer6, Edwyn B L Lo1, Cherry Leung1, Evelyne Lima-Fernandes1, Nicholas M Pedley1, Fraser Soares1, Sophie McGibbon7, Housheng Hansen He6, Aaron Pollet2, Trevor J Pugh8, Benjamin Haibe-Kains9, Quaid Morris10, Miguel Ramalho-Santos11, Sidhartha Goyal12, Jason Moffat13, Catherine A O'Brien14.
Abstract
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.Entities:
Keywords: MRD; autophagy; barcode; chemotherapy; colorectal cancer; diapause; drug tolerant persisters; equipotent; mTOR; slow-cycling
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Year: 2021 PMID： 33417860 PMCID： PMC8437243 DOI： 10.1016/j.cell.2020.11.018
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582