Drug-resilient cancer cell phenotype is acquired via polyploidization associated with early stress response coupled to HIF-2α transcriptional regulation

Carroll, Christopher; Manaprasertsak, Auraya; Boffelli Castro, Arthur; van den Bos, Hilda; Spierings, Diana C.J.; Wardenaar, René; Bukkuri, Anuraag; Engström, Niklas; Baratchart, Etienne; Yang, Minjun; Biloglav, Andrea; Cornwallis, Charlie; Johansson, Bertil; Hagerling, Catharina; Arsenian-Henriksson, Marie; Paulsson, Kajsa; Amend, Sarah R.; Mohlin, Sofie; Foijer, Floris; McIntyre, Alan; Pienta, Kenneth J.; Hammarlund, Emma U.

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 HIF-2α. We found altered chromatin accessibility, ablated expression of RB1, and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF-2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF-2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF-2α in stress-response by polyploidy suggest a novel avenue for tackling chemotherapy-induced resistance in cancer.

• Journal Article Type: Article
• Acceptance Date: Feb 16, 2024
• Online Publication Date: Feb 22, 2024
• Publication Date: Mar 1, 2024
• Deposit Date: Feb 26, 2024
• Publicly Available Date: Feb 28, 2024
• Journal: Cancer Research Communications
• Print ISSN: 2767-9764
• Electronic ISSN: 2767-9764
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 4
• Issue: 3
• Pages: 691-705
• DOI: https://doi.org/10.1158/2767-9764.crc-23-0396
• Keywords: General Earth and Planetary Sciences
• Public URL: https://nottingham-repository.worktribe.com/output/31618779
• Publisher URL: https://aacrjournals.org/cancerrescommun/article/doi/10.1158/2767-9764.CRC-23-0396/734848/Drug-resilient-cancer-cell-phenotype-is-acquired
• Additional Information: This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.