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Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation

Carroll, Christopher LU ; Manaprasertsak, Auraya LU ; Castro, Arthur Boffelli LU orcid ; Van den Bos, Hilda ; Spierings, Diana C.J. ; Wardenaar, René ; Bukkuri, Anuraag LU ; Engström, Niklas LU ; Baratchart, Etienne LU and Yang, Minjun LU , et al. (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.

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organization
publishing date
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}},
}