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

Autor:	Rehman SK; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Haynes J; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Collignon E; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada., Brown KR; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada., Wang Y; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Nixon AML; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada., Bruce JP; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Wintersinger JA; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada; Vector Institute, Toronto, ON M5G 1M1, Canada., Singh Mer A; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Lo EBL; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Leung C; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Lima-Fernandes E; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Pedley NM; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., Soares F; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada., McGibbon S; Department of Physics, University of Toronto, Toronto, ON M5S 1A7, Canada., He HH; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Pollet A; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada., Pugh TJ; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada; Clinical Genomics Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Haibe-Kains B; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada., Morris Q; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada; Vector Institute, Toronto, ON M5G 1M1, Canada; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Ramalho-Santos M; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: mrsantos@lunenfeld.ca., Goyal S; Department of Physics, University of Toronto, Toronto, ON M5S 1A7, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: goyal@physics.utoronto.ca., Moffat J; Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3E1, Canada. Electronic address: j.moffat@utoronto.ca., O'Brien CA; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Surgery, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: cobrien@uhnresearch.ca.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Jan 07; Vol. 184 (1), pp. 226-242.e21.
DOI:	10.1016/j.cell.2020.11.018
Abstrakt:	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. Competing Interests: Declaration of Interests J.M. is a shareholder in Northern Biologics and Pionyr Immunotherapeutics and an advisor for Century Therapeutics and Aelian Biotechnology. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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