Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation
(2024) In Cancer Research Communications 4(3). p.691-705- 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... (More)
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.
(Less)
- author
- organization
-
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- Molecular Evolution (research group)
- LUCC: Lund University Cancer Centre
- Childhood Cancer Research Unit (research group)
- Paediatrics (Lund)
- Division of Translational Cancer Research
- Aneuploidy in cancer (research group)
- Division of Clinical Genetics
- Genetic and epigenetic studies of pediatric leukemia (research group)
- Functional ecology
- Molecular Ecology and Evolution Lab (research group)
- EpiHealth: Epidemiology for Health
- Lithosphere and Biosphere Science
- publishing date
- 2024-03
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cancer Research Communications
- volume
- 4
- issue
- 3
- pages
- 15 pages
- external identifiers
-
- scopus:85195024933
- pmid:38385626
- DOI
- 10.1158/2767-9764.CRC-23-0396
- language
- English
- LU publication?
- yes
- id
- b4b607d1-06a2-4a91-92ac-7acb481d3b2d
- date added to LUP
- 2024-09-02 10:14:54
- date last changed
- 2024-09-03 03:00:11
@article{b4b607d1-06a2-4a91-92ac-7acb481d3b2d, abstract = {{<p>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.</p>}}, author = {{Carroll, Christopher and Manaprasertsak, Auraya and Castro, Arthur Boffelli and Van den Bos, Hilda and Spierings, Diana C.J. and Wardenaar, René and Bukkuri, Anuraag and Engström, Niklas and Baratchart, Etienne and Yang, Minjun and Biloglav, Andrea and Cornwallis, Charlie K. and Johansson, Bertil and Hagerling, Catharina and Arsenian-Henriksson, Marie and Paulsson, Kajsa and Amend, Sarah R. and Mohlin, Sofie and Foijer, Floris and McIntyre, Alan and Pienta, Kenneth J. and Hammarlund, Emma U.}}, language = {{eng}}, number = {{3}}, pages = {{691--705}}, series = {{Cancer Research Communications}}, title = {{Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation}}, url = {{http://dx.doi.org/10.1158/2767-9764.CRC-23-0396}}, doi = {{10.1158/2767-9764.CRC-23-0396}}, volume = {{4}}, year = {{2024}}, }