Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation
Carroll, C., Manaprasertsak, A., Boffelli Castro, A. , van den Bos, H., Spierings, D. C. J., Wardenaar, R., Bukkuri, A. 
ORCID: 0000-0002-3616-626X, Engström, N., Baratchart, E., Yang, M., Biloglav, A., Cornwallis, C. K., Johansson, B., Hagerling, C., Arsenian-Henriksson, M., Paulsson, K., Amend, S. R., Mohlin, S., Foijer, F., McIntyre, A., Pienta, K. J. & Hammarlund, E. U. (2024).
Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.
Cancer Research Communications, 4(3),
pp. 691-705.
doi: 10.1158/2767-9764.crc-23-0396
Abstract
Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer.
| Publication Type: | Article |
|---|---|
| Additional Information: | © 2024 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. |
| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica |
| Departments: | School of Science & Technology School of Science & Technology > Department of Mathematics |
| SWORD Depositor: |
Available under License Creative Commons Attribution.
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