TY - JOUR
T1 - Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division
AU - Replogle, John Michael
AU - Zhou, Wen
AU - Amaro, Adrianna E.
AU - McFarland, James M.
AU - Villalobos-Ortiz, Mariana
AU - Ryan, Jeremy
AU - Letai, Anthony
AU - Yilmaz, Omer
AU - Sheltzer, Jason
AU - Lippard, Stephen J.
AU - Ben-David, Uri
AU - Amon, Angelika
N1 - Funding Information: ACKNOWLEDGMENTS. We thank Pei-Hsin Hsu for taking pictures of the mice in this paper. We thank Michael Hemann and members of the A.A. laboratory for their helpful comments and discussion regarding this project and manuscript. We thank the Swanson Biotechnology Center for equipment, resources, and technical support, specifically the Koch Institute Flow Cytometry core and High Throughput Sciences core. J.M.R. was supported by a David H. Koch predoctoral fellowship. This work was supported by NIH grant CA206157 to A.A., who is an Investigator of the Howard Hughes Medical Institute; the Paul F. Glenn Center for Biology of Aging Research at MIT; and the Ludwig Center at MIT. U.B.-D. is an Azrieli Faculty Fellow. This work was also supported by NIH grants CA034992 to O.Y. and S.J.L. and CA211184 to O.Y., who is a Pew Scholar. A.L. is a Ludwig Investigator.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition—G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.
AB - Aneuploidy, defined as whole chromosome gains and losses, is associated with poor patient prognosis in many cancer types. However, the condition causes cellular stress and cell cycle delays, foremost in G1 and S phase. Here, we investigate how aneuploidy causes both slow proliferation and poor disease outcome. We test the hypothesis that aneuploidy brings about resistance to chemotherapies because of a general feature of the aneuploid condition—G1 delays. We show that single chromosome gains lead to increased resistance to the frontline chemotherapeutics cisplatin and paclitaxel. Furthermore, G1 cell cycle delays are sufficient to increase chemotherapeutic resistance in euploid cells. Mechanistically, G1 delays increase drug resistance to cisplatin and paclitaxel by reducing their ability to damage DNA and microtubules, respectively. Finally, we show that our findings are clinically relevant. Aneuploidy correlates with slowed proliferation and drug resistance in the Cancer Cell Line Encyclopedia (CCLE) dataset. We conclude that a general and seemingly detrimental effect of aneuploidy, slowed proliferation, provides a selective benefit to cancer cells during chemotherapy treatment.
KW - Aneuploidy
KW - Cell cycle
KW - Chemotherapy resistance
KW - Cisplatin
KW - Paclitaxel
UR - http://www.scopus.com/inward/record.url?scp=85097210341&partnerID=8YFLogxK
U2 - 10.1073/pnas.2009506117
DO - 10.1073/pnas.2009506117
M3 - مقالة
C2 - 33203674
SN - 0027-8424
VL - 117
SP - 30566
EP - 30576
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 48
ER -
