Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies

Lukow, Devon A, Sausville, Erin L, Suri, Pavit, Chunduri, Narendra Kumar, Wieland, Angela, Leu, Justin, Smith, Joan C, Girish, Vishruth, Kumar, Ankith A, Kendall, Jude, Wang, Zihua, Storchova, Zuzana, Sheltzer, Jason M (August 2021) Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental Cell. ISSN 1534-5807

Abstract

Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosome bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomes, structure and function > chromosome diseases & disorders > cancer > drugs and therapies organs, tissues, organelles, cell types and functions
CSHL Authors:	Sausville, Erin L Leu, Justin Girish, Vishruth Kendall, Jude T. Wang, Zihua Sheltzer, Jason
Communities:	CSHL labs > Sheltzer lab CSHL labs > Wigler lab CSHL Cancer Center Program CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Shared Resources > Flow Cytometry Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	2 August 2021
Date Deposited:	11 Aug 2021 13:44
Last Modified:	13 Feb 2024 18:45
PMCID:	PMC8933054
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/40318

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