Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy

• Published in: Cell Vol. 184; no. 1; pp. 226 - 242.e21
• Main Authors: Rehman, Sumaiyah K., Haynes, Jennifer, Collignon, Evelyne, Brown, Kevin R., Wang, Yadong, Nixon, Allison M.L., Bruce, Jeffrey P., Wintersinger, Jeffrey A., Singh Mer, Arvind, Lo, Edwyn B.L., Leung, Cherry, Lima-Fernandes, Evelyne, Pedley, Nicholas M., Soares, Fraser, McGibbon, Sophie, He, Housheng Hansen, Pollet, Aaron, Pugh, Trevor J., Haibe-Kains, Benjamin, Morris, Quaid, Ramalho-Santos, Miguel, Goyal, Sidhartha, Moffat, Jason, O’Brien, Catherine A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.01.2021
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; autophagy; Autophagy - drug effects; Autophagy - genetics; barcode; Cell Line, Tumor; chemotherapy; Clone Cells; colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Diapause; Drug Resistance, Neoplasm - drug effects; drug tolerant persisters; Embryo, Mammalian - drug effects; Embryo, Mammalian - metabolism; equipotent; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genetic Heterogeneity - drug effects; Humans; Irinotecan - pharmacology; Irinotecan - therapeutic use; Mice; Mice, Inbred NOD; Mice, SCID; Models, Biological; MRD; mTOR; Signal Transduction - drug effects; slow-cycling; Up-Regulation - drug effects; Up-Regulation - genetics; Xenograft Model Antitumor Assays; equipotent; colorectal cancer; autophagy; drug tolerant persisters; diapause; mTOR; slow-cycling; chemotherapy; barcode; MRD
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.11.018

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. [Display omitted] •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 Any cancer cell has the ability to enter a drug-tolerant persister state in response to chemotherapy regimens by acquiring a reversible functional state akin to diapause.