Data from Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation
Year: 2024
Type: other
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. Significance: In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.
Authors: Christopher Carroll, Auraya Manaprasertsak, Arthur Boffelli Castro, Hilda van den Bos, Diana C.J. Spierings, René Wardenaar, Anuraag Bukkuri, Niklas Engström, Etienne Baratchart, Minjun Yang, Andrea Biloglav, Charlie K. Cornwallis, Bertil Johansson, Catharina Hagerling, Marie Arsenian-Henriksson, Kajsa Paulsson, Sarah R. Amend, Sofie Mohlin, Floris Foijer, Alan McIntyre, Kenneth J. Pienta, Emma U. Hammarlund
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4392550529