Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy.
Animals
Antineoplastic Agents
/ pharmacology
Autophagy
/ drug effects
Cell Line, Tumor
Clone Cells
Colorectal Neoplasms
/ drug therapy
Diapause
Drug Resistance, Neoplasm
/ drug effects
Embryo, Mammalian
/ drug effects
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
/ drug effects
Genetic Heterogeneity
/ drug effects
Humans
Irinotecan
/ pharmacology
Mice, Inbred NOD
Mice, SCID
Models, Biological
Signal Transduction
/ drug effects
Up-Regulation
/ drug effects
Xenograft Model Antitumor Assays
MRD
autophagy
barcode
chemotherapy
colorectal cancer
diapause
drug tolerant persisters
equipotent
mTOR
slow-cycling
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
07 01 2021
07 01 2021
Historique:
received:
07
02
2020
revised:
25
08
2020
accepted:
10
11
2020
entrez:
8
1
2021
pubmed:
9
1
2021
medline:
26
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33417860
pii: S0092-8674(20)31535-X
doi: 10.1016/j.cell.2020.11.018
pmc: PMC8437243
mid: NIHMS1732990
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Irinotecan
7673326042
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
226-242.e21Subventions
Organisme : CIHR
ID : FDN-148479
Pays : Canada
Organisme : NCI NIH HHS
ID : R01 CA148761
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : CIHR
ID : MOP-142375
Pays : Canada
Organisme : CIHR
ID : 420231
Pays : Canada
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests J.M. is a shareholder in Northern Biologics and Pionyr Immunotherapeutics and an advisor for Century Therapeutics and Aelian Biotechnology.
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