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Aneuploidy Increases Resistance to Chemotherapeutics by Antagonizing Cell Division

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Aneuploidy Increases Resistance to Chemotherapeutics by Antagonizing Cell Division Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division John Michael Reploglea,1, Wen Zhoua,b, Adrianna E. Amaroa, James M. McFarlandc, Mariana Villalobos-Ortizd, Jeremy Ryand, Anthony Letaid,e, Omer Yilmaza, Jason Sheltzerf, Stephen J. Lipparda,b, Uri Ben-Davidg, and Angelika Amona,h,2 aDavid H. Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139; bDepartment of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139; cBroad Institute of MIT and Harvard, Cambridge, MA 02139; dDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; eDepartment of Medicine, Harvard Medical School, Boston, MA 02115; fCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; gDepartment of Human Molecular Genetics and Biochemistry, Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; and hHHMI, Massachusetts Institute of Technology, Cambridge, MA 02139 Contributed by Angelika Amon, September 24, 2020 (sent for review May 13, 2020; reviewed by Andrew J. Holland and Geert J. P. L. Kops) Aneuploidy, defined as whole chromosome gains and losses, is resistance, and patients with high CIN tumors have a worse associated with poor patient prognosis in many cancer types. How- prognosis than those with chromosomally stable cancers (24). ever, the condition causes cellular stress and cell cycle delays, The connection between CIN and drug resistance has been at- foremost in G1 and S phase. Here, we investigate how aneuploidy tributed to increased heterogeneity and, hence, subclones within causes both slow proliferation and poor disease outcome. We test the the tumor that are drug resistant. However, other studies have hypothesis that aneuploidy brings about resistance to chemother- found that extremely high levels of CIN increase patient survival apies because of a general feature of the aneuploid condition—G1 (25–27). Extreme aneuploidy stress could synergize with the delays. We show that single chromosome gains lead to increased antiproliferative effects of cancer drugs and may prevent cells resistance to the frontline chemotherapeutics cisplatin and paclitaxel. from “holding onto” a drug-resistant karyotype. Furthermore, G1 cell cycle delays are sufficient to increase chemother- Specific aneuploidies also drive drug resistance in human cancer apeutic resistance in euploid cells. Mechanistically, G1 delays increase cells. In DLD1, a colon cancer cell line, two trisomic derivatives drug resistance to cisplatin and paclitaxel by reducing their ability to (trisomy 7 and trisomy 13) grew better than their euploid coun- damage DNA and microtubules, respectively. Finally, we show that terpart when treated with 5-fluorouracil (28). Whether aneuploidy- GENETICS our findings are clinically relevant. Aneuploidy correlates with slowed induced copy number changes of specific genes or some general proliferation and drug resistance in the Cancer Cell Line Encyclopedia feature of the aneuploid state drive chemotherapy resistance is (CCLE) dataset. We conclude that a general and seemingly detrimen- currently unknown. Here we investigate this question, focusing on tal effect of aneuploidy, slowed proliferation, provides a selective cis-diamminedichloroplatinum(II) (cisplatin) and paclitaxel, two benefit to cancer cells during chemotherapy treatment. front line chemotherapeutics that are used to treat highly aneuploid cancers such as bladder, ovarian, testicular, breast, and nonsmall aneuploidy | cell cycle | chemotherapy resistance | cisplatin | paclitaxel cell lung cancer. We show that aneuploidy causes resistance to these chemotherapeutics through a general feature of the aneuploid arly observations of cancer noted that cancer cells often condition: slowed proliferation. Equalizing growth of aneuploid Epossess an abnormal number of chromosomes. About 90% of and euploid control cells eliminates differences in drug resistance solid tumors are aneuploid, meaning they harbor a chromosome between them. Finally, we provide evidence that our findings count that is not a multiple of the haploid complement. Thus, are clinically relevant. Aneuploidy and chromosomal instability aneuploidy is more common than any individual gene mutations in cancer (1). This abnormal DNA content leads to changes in RNA Significance and protein expression and many phenotypic changes (2–5). No- tably, aneuploidy is significantly associated with poor patient Aneuploidy, or an imbalanced chromosome content, is a hall- prognoses, both in pan-cancer analyses and cancer-type-specific mark of cancer. Paradoxically, aneuploidy is associated both – studies (6 13). with poor prognosis in cancer and with slow growth in primary Despite its prevalence in cancer, recent studies have revealed that cells. Here, we bridge these two seemingly contradictory ob- aneuploidy causes a wide variety of cellular stresses. As changes in servations: the cell cycle defects caused by aneuploidy protect gene copy number generally result in changes in gene expression, cancer cells from chemotherapeutic damage. Our study may stoichiometric imbalances in protein complexes lead to increased inform treatment decisions by impacting our understanding of protein misfolding and proteotoxic stress due to an increased de- how sensitive a particular tumor may be to certain mand for protein quality-control machinery (14–16). Aneuploidy chemotherapies. also alters the metabolic landscape of cells and causes genome in- stability (5, 17–20). These aneuploidy-associated stresses lead to cell Author contributions: J.M.R., J.S., U.B.-D., and A.A. designed research; J.M.R., W.Z., A.E.A., cycle changes and slow proliferation (4, 21). Specifically, aneuploidy J.M.M., M.V.-O., J.R., and U.B.-D. performed research; A.L., O.Y., and S.J.L. contributed Saccharomyces cerevisiae new reagents/analytic tools; A.A. provided resources; J.M.R., W.Z., A.E.A., J.M.M., and causes G1 delays in the yeast, ,and U.B.-D. analyzed data; and J.M.R. and A.A. wrote the paper. lengthens G1 and S phase in mammalian cells under most cir- Reviewers: A.J.H., Johns Hopkins University Medical School; and G.J.P.L.K., Hubrecht cumstances (20, 22, 23). Institute. How can a feature of cancer be associated with poor patient Competing interest statement: A.A. and G.J.P.L.K. are coapplicants on a grant. They have prognosis if it slows cancer’s growth? One possibility is that an- not collaborated directly on this project. euploidy increases a tumor’s resistance to treatment. In cancer, Published under the PNAS license. drug resistance has, among other parameters, been associated 1To whom correspondence may be addressed. Email: [email protected]. with cells missegregating chromosomes at a higher rate, a phe- 2Deceased October 29, 2020. nomenon known as chromosomal instability (CIN). CIN and This article contains supporting information online at https://www.pnas.org/lookup/suppl/ aneuploidy exhibit positive feedback, with each driving the other. doi:10.1073/pnas.2009506117/-/DCSupplemental. Colon cancer cell lines with CIN have increased multidrug www.pnas.org/cgi/doi/10.1073/pnas.2009506117 PNAS Latest Articles | 1of11 Downloaded by guest on October 1, 2021 correlate with slowed proliferation and drug resistance in the A Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude Cisplatin Cisplatin that proliferative index is a major determinant of chemotherapy 100 100 ’ efficacy and that aneuploidy s role in causing chemotherapy re- 80 80 **** sistance is mediated at least in part by its adverse effects on cell 60 *** 60 proliferation. 40 40 Results 20 20 Trisomy Increases Resistance to Frontline Chemotherapeutics. To test Adjusted % Living 0 Adjusted % Living 0 how aneuploidy affects chemotherapeutic response, we chose WT Ts13 WT Ts16 two commonly used chemotherapies that inhibit cell prolifera- MEF MEF tion by very different mechanisms: cisplatin, a platinum-based B Paclitaxel C No Drug Cisplatin drug that causes DNA damage by binding DNA in a 100 non-cell-cycle-specific manner, and paclitaxel (Taxol), a micro- 80 tubule stabilizing agent that arrests cells in mitosis. For cisplatin, ** WT *** we tested the response of multiple trisomic mouse embryonic 60 NS *** p53DD fibroblast (MEF) cell lines and their euploid littermate controls 40 (4). Because MEFs are not very responsive to paclitaxel, we 20 tested the efficacy of paclitaxel against a pseudodiploid colon Ts16 Adjusted % Living 0 cancer cell line, HCT116, and four aneuploid derivatives of this WT Ts3 Ts5 Tet5 Ts8 p53DD cell line (22). HCT116 To determine how aneuploidy impacts cisplatin response, we D compared the drug response of four trisomy 13 MEF lines (Ts13) Cisplatin Cisplatin 100 and four trisomy 16 MEF lines (Ts16), all from different litters, 100 *** to their euploid littermate controls. We treated cells with cis- 80 **** μ 80 platin (15 M) for 48 h and then identified living, dead, and early 60 apoptotic cell populations by flow cytometry using Annexin V 60 and DAPI staining. We found that in three of the four trisomy 13 40 40 lines a greater percentage of cells were alive following drug 20 20 treatment compared to their euploid controls (Fig. 1A and SI Adjusted % Living 0 Adjusted % Living 0 Appendix, Fig. S1A). Similarly, all four trisomy 16 cell lines WT Ts13 WT Ts16 exhibited increased survival following cisplatin treatment relative p53DD p53DD p53DD p53DD to euploid controls (Fig. 1A and SI Appendix, Fig. S1B). We MEF MEF conclude that trisomies 13 and 16 confer decreased cisplatin
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