Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Marica Rosaria Ippolito; Valentino Martis; Sara Martin; Andréa E. Tijhuis; Christy Hong; René Wardenaar; Marie Dumont; Johanna Zerbib; Diana C.J. Spierings; Daniele Fachinetti; Uri Ben-David; Floris Foijer; Stefano Santaguida

doi:10.1016/j.devcel.2021.07.006

Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Marica Rosaria Ippolito, Valentino Martis, Sara Martin, Andréa E. Tijhuis, Christy Hong, René Wardenaar, Marie Dumont, Johanna Zerbib, Diana C.J. Spierings, Daniele Fachinetti, Uri Ben-David, Floris Foijer, Stefano Santaguida^*

^*Corresponding author for this work

Human Molecular Genetics Biochemistry

Research output: Contribution to journal › Article › peer-review

111 Scopus citations

Abstract

Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.

Original language	English
Pages (from-to)	2440-2454.e6
Journal	Developmental Cell
Volume	56
Issue number	17
DOIs	https://doi.org/10.1016/j.devcel.2021.07.006
State	Published - 13 Sep 2021

Funding

Funders	Funder number
Anna Obenauf and Christian Umkehrer
City of Paris
Devon Lukow and Jason Sheltzer
DoD CDMRP	CA191148
Giuseppina De Feudis
Mike Hemann
Israel Cancer Research Fund
United States - Israel Binational Science Foundation	2019228
Massachusetts Institute of Technology
Cold Spring Harbor Laboratory
Istituto Europeo di Oncologia
University of Manchester
Human Frontier Science Program
Fondazione Cariplo
Ministero della Salute	5×1000
Ministero dell’Istruzione, dell’Università e della Ricerca
Israel Cancer Association	20200111
KWF Kankerbestrijding	2017-RUG-11457
Centre National de la Recherche Scientifique
Associazione Italiana per la Ricerca sul Cancro	21665, GR-2018-12367077
Azrieli Foundation
Instituto Mexicano del Petróleo

Keywords

aneuploidy
cancer
chemotherapy
drug resistance
genome instability

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.devcel.2021.07.006

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Ippolito, M. R., Martis, V., Martin, S., Tijhuis, A. E., Hong, C., Wardenaar, R., Dumont, M., Zerbib, J., Spierings, D. C. J., Fachinetti, D., Ben-David, U., Foijer, F., & Santaguida, S. (2021). Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy. Developmental Cell, 56(17), 2440-2454.e6. https://doi.org/10.1016/j.devcel.2021.07.006

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title = "Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy",

abstract = "Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.",

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Ippolito, MR, Martis, V, Martin, S, Tijhuis, AE, Hong, C, Wardenaar, R, Dumont, M, Zerbib, J, Spierings, DCJ, Fachinetti, D, Ben-David, U, Foijer, F & Santaguida, S 2021, 'Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy', Developmental Cell, vol. 56, no. 17, pp. 2440-2454.e6. https://doi.org/10.1016/j.devcel.2021.07.006

TY - JOUR

T1 - Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

AU - Ippolito, Marica Rosaria

AU - Martis, Valentino

AU - Martin, Sara

AU - Tijhuis, Andréa E.

AU - Hong, Christy

AU - Wardenaar, René

AU - Dumont, Marie

AU - Zerbib, Johanna

AU - Spierings, Diana C.J.

AU - Fachinetti, Daniele

AU - Ben-David, Uri

AU - Foijer, Floris

AU - Santaguida, Stefano

PY - 2021/9/13

Y1 - 2021/9/13

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AB - Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.

KW - aneuploidy

KW - cancer

KW - chemotherapy

KW - drug resistance

KW - genome instability

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Gene copy-number changes and chromosomal instability induced by aneuploidy confer resistance to chemotherapy

Abstract

Funding

Keywords

UN SDGs

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