Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division
© 2020 National Academy of Sciences. All rights reserved. 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 ho...
| Main Authors: | , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2021
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| Online Access: | https://hdl.handle.net/1721.1/133334 |
| _version_ | 1826209188695506944 |
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| author | Replogle, John Michael Zhou, Wen Amaro, Adrianna E McFarland, James M Villalobos-Ortiz, Mariana Ryan, Jeremy Letai, Anthony Yilmaz, Omer Sheltzer, Jason Lippard, Stephen J Ben-David, Uri Amon, Angelika |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Replogle, John Michael Zhou, Wen Amaro, Adrianna E McFarland, James M Villalobos-Ortiz, Mariana Ryan, Jeremy Letai, Anthony Yilmaz, Omer Sheltzer, Jason Lippard, Stephen J Ben-David, Uri Amon, Angelika |
| author_sort | Replogle, John Michael |
| collection | MIT |
| description | © 2020 National Academy of Sciences. All rights reserved. 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. |
| first_indexed | 2024-09-23T14:18:36Z |
| format | Article |
| id | mit-1721.1/133334 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:18:36Z |
| publishDate | 2021 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1333342024-02-02T19:25:27Z Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division Replogle, John Michael Zhou, Wen Amaro, Adrianna E McFarland, James M Villalobos-Ortiz, Mariana Ryan, Jeremy Letai, Anthony Yilmaz, Omer Sheltzer, Jason Lippard, Stephen J Ben-David, Uri Amon, Angelika Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Department of Chemistry Howard Hughes Medical Institute © 2020 National Academy of Sciences. All rights reserved. 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. 2021-10-27T19:52:11Z 2021-10-27T19:52:11Z 2020 2021-08-05T14:50:06Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/133334 en 10.1073/pnas.2009506117 Proceedings of the National Academy of Sciences of the United States of America Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Proceedings of the National Academy of Sciences PNAS |
| spellingShingle | Replogle, John Michael Zhou, Wen Amaro, Adrianna E McFarland, James M Villalobos-Ortiz, Mariana Ryan, Jeremy Letai, Anthony Yilmaz, Omer Sheltzer, Jason Lippard, Stephen J Ben-David, Uri Amon, Angelika Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| title | Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| title_full | Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| title_fullStr | Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| title_full_unstemmed | Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| title_short | Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| title_sort | aneuploidy increases resistance to chemotherapeutics by antagonizing cell division |
| url | https://hdl.handle.net/1721.1/133334 |
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