Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint
Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint
Abstract Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. Here, we mapped the aneuploidy landscapes of ~1,000 human cancer cell lines and classified them by their degree of aneuploidy. Next, we performed a comprehensive analysis of large-scale genetic and chemical perturbation screens, in order to compare the cellular vulnerabilities between near-diploid and highly-aneuploid cancer cells. We identified and validated an increased sensitivity of aneuploid cancer cells to genetic perturbation of core components of the spindle assembly checkpoint (SAC), which ensures the proper segregation of chromosomes during mitosis. Surprisingly, we also found highly-aneuploid cancer cells to be less sensitive to short-term exposures to multiple inhibitors of the SAC regulator TTK. To resolve this paradox and to uncover its mechanistic basis, we established isogenic systems of near-diploid cells and their aneuploid derivatives. Using both genetic and chemical inhibition of BUB1B, MAD2 and TTK, we found that the cellular response to SAC inhibition depended on the duration of the assay, as aneuploid cancer cells became increasingly more sensitive to SAC inhibition over time. The increased ability of aneuploid cells to slip from mitotic arrest and to keep dividing in the presence of SAC inhibition was coupled to aberrant spindle geometry and dynamics. This resulted in a higher prevalence of mitotic defects, such as multipolar spindles, micronuclei formation and failed cytokinesis. Therefore, although aneuploid cancer cells can overcome SAC inhibition more readily than diploid cells, the proliferation of the resultant aberrant cells is jeopardized. At the molecular level, analysis of spindle proteins identified a specific mitotic kinesin, KIF18A, whose levels were drastically reduced in aneuploid cancer cells. Aneuploid cancer cells were particularly vulnerable to KIF18A depletion, and KIF18A overexpression restored the sensitivity of aneuploid cancer cells to SAC inhibition. In summary, we identified an increased vulnerability of aneuploid cancer cells to SAC inhibition and explored its cellular and molecular underpinnings. Our results reveal a novel synthetic lethal interaction between aneuploidy and the SAC, which may have direct therapeutic relevance for the clinical application of SAC inhibitors.
McFarland James M.、Marquis Carolyn、Bernhard Sara V.、Malaby Heidi L.H.、Kazachkova Mariya、Bass Adam J.、Stumpff Jason、Ben-David Uri、Laue Kathrin、Ippolito Marica R.、Storchova Zuzana、Nagaraja Ankur、Golub Todd R.、Lyons Nicholas、Santaguida Stefano、Beroukhim Rameen、Tang Helen、Abdusamad Mai、Jones Andrew、Cohen-Sharir Yael
Cancer Program, Broad Institute of MIT and Harvard, CambridgeDepartment of Molecular Physiology and Biophysics, University of VermontDepartment of Molecular Genetics, TU KaiserlauternDepartment of Molecular Physiology and Biophysics, University of VermontCancer Program, Broad Institute of MIT and Harvard, CambridgeCancer Program, Broad Institute of MIT and Harvard, Cambridge||Dana Farber Cancer Institute, BostonDepartment of Molecular Physiology and Biophysics, University of VermontDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv UniversityDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv UniversityDepartment of Experimental Oncology at IEO, European Institute of Oncology IRCCSDepartment of Molecular Genetics, TU KaiserlauternCancer Program, Broad Institute of MIT and Harvard, Cambridge||Dana Farber Cancer Institute, BostonCancer Program, Broad Institute of MIT and Harvard, Cambridge||Department of Experimental Oncology at IEO, European Institute of Oncology IRCCSCancer Program, Broad Institute of MIT and Harvard, CambridgeDepartment of Experimental Oncology at IEO, European Institute of Oncology IRCCS||Department of Oncology and Hemato-Oncology, University of MilanCancer Program, Broad Institute of MIT and Harvard, Cambridge||Dana Farber Cancer Institute, BostonCancer Program, Broad Institute of MIT and Harvard, CambridgeCancer Program, Broad Institute of MIT and Harvard, CambridgeCancer Program, Broad Institute of MIT and Harvard, CambridgeDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University
肿瘤学基础医学分子生物学
McFarland James M.,Marquis Carolyn,Bernhard Sara V.,Malaby Heidi L.H.,Kazachkova Mariya,Bass Adam J.,Stumpff Jason,Ben-David Uri,Laue Kathrin,Ippolito Marica R.,Storchova Zuzana,Nagaraja Ankur,Golub Todd R.,Lyons Nicholas,Santaguida Stefano,Beroukhim Rameen,Tang Helen,Abdusamad Mai,Jones Andrew,Cohen-Sharir Yael.Selective vulnerability of aneuploid human cancer cells to inhibition of the spindle assembly checkpoint[EB/OL].(2025-03-28)[2025-04-25].https://www.biorxiv.org/content/10.1101/2020.06.18.159038.点此复制
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