title: Emergence of drug tolerance in cancer cell populations: an evolutionary outcome of selection, nongenetic instability, and stress-induced adaptation.
abstract: In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells, which display markers associated with stem cell-like cancer cells. After a period of time, some of the surviving cells were observed to change their phenotype to resume normal proliferation and eventually repopulate the sample. Furthermore, the drug-tolerant cells could be drug resensitized following drug washout. Here, we propose a theoretical mechanism for the transient emergence of such drug tolerance. In this framework, we formulate an individual-based model and an integro-differential equation model of reversible phenotypic evolution in a cell population exposed to cytotoxic drugs. The outcomes of both models suggest that nongenetic instability, stress-induced adaptation, selection, and the interplay between these mechanisms can push an actively proliferating cell population to transition into a weakly proliferative and drug-tolerant state. Hence, the cell population experiences much less stress in the presence of the drugs and, in the long run, reacquires a proliferative phenotype, due to phenotypic fluctuations and selection pressure. These mechanisms can also reverse epigenetic drug tolerance following drug washout. Our study highlights how the transient appearance of the weakly proliferative and drug-tolerant cells is related to the use of high-dose therapy. Furthermore, we show how stem-like characteristics can act to stabilize the transient, weakly proliferative, and drug-tolerant subpopulation for a longer time window. Finally, using our models as in silico laboratories, we propose new testable hypotheses that could help uncover general principles underlying the emergence of cancer drug tolerance.
authors: INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, Le Chesnay Cedex, France. Sorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. CNRS, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. rebecca.chisholm@inria.fr.
authors: Rebecca H
authors: RH
authors: Chisholm
authors: INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, Le Chesnay Cedex, France. Sorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. CNRS, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. CMLA, ENS Cachan, CNRS, PRES UniverSud, 61, Avenue du Président Wilson, Cachan Cedex, France.
authors: Tommaso
authors: T
authors: Lorenzi
authors: INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, Le Chesnay Cedex, France. Sorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. CNRS, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France.
authors: Alexander
authors: A
authors: Lorz
authors: Sorbonne Universités, UPMC Univ Paris 06, Paris, France. INSERM, UMR_S 938, Laboratory of Cancer Biology and Therapeutics, Paris, France.
authors: Annette K
authors: AK
authors: Larsen
authors: INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, Le Chesnay Cedex, France. Sorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. CNRS, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France.
authors: Luís Neves
authors: LN
authors: de Almeida
authors: Sorbonne Universités, UPMC Univ Paris 06, Paris, France. INSERM, UMR_S 938, Laboratory of Cancer Biology and Therapeutics, Paris, France.
authors: Alexandre
authors: A
authors: Escargueil
authors: INRIA-Paris-Rocquencourt, MAMBA Team, Domaine de Voluceau, Le Chesnay Cedex, France. Sorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France. CNRS, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, France.
authors: Jean
authors: J
authors: Clairambault
mesh_terms: D000222:Adaptation, Physiological; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004361:Drug Tolerance; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D013312:Stress, Physiological