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

Sumaiyah K Rehman; Jennifer Haynes; Evelyne Collignon; Kevin R Brown; Yadong Wang; Allison M L Nixon; Jeffrey P Bruce; Jeffrey A Wintersinger; Arvind Singh Mer; Edwyn B L Lo; Cherry Leung; Evelyne Lima-Fernandes; Nicholas M Pedley; Fraser Soares; Sophie McGibbon; Housheng Hansen He; Aaron Pollet; Trevor J Pugh; Benjamin Haibe-Kains; Quaid Morris; Miguel Ramalho-Santos; Sidhartha Goyal; Jason Moffat; Catherine A O'Brien

doi:10.1016/j.cell.2020.11.018

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

Cell. 2021 Jan 7;184(1):226-242.e21. doi: 10.1016/j.cell.2020.11.018.

Authors

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

Affiliations

¹ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
² Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada.
³ Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
⁵ 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.
⁶ Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
⁷ Department of Physics, University of Toronto, Toronto, ON M5S 1A7, Canada.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.
¹³ 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.
¹⁴ 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.

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.

Keywords: MRD; autophagy; barcode; chemotherapy; colorectal cancer; diapause; drug tolerant persisters; equipotent; mTOR; slow-cycling.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use*
Autophagy / drug effects
Autophagy / genetics
Cell Line, Tumor
Clone Cells
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology
Diapause*
Drug Resistance, Neoplasm* / drug effects
Embryo, Mammalian / drug effects
Embryo, Mammalian / metabolism
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
Signal Transduction / drug effects
Up-Regulation / drug effects
Up-Regulation / genetics
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Irinotecan

Abstract

Publication types

MeSH terms

Substances

Grants and funding