| 1. |
- Carroll, Christopher, et al.
(författare)
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Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation
- 2024
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Ingår i: Cancer Research Communications. - 2767-9764. ; 4:3, s. 691-705
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Leggett, Helen C, et al.
(författare)
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Growth rate, transmission mode and virulence in human pathogens
- 2017
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Ingår i: Philosophical Transactions of the Royal Society B: Biological Sciences. - : The Royal Society. - 0962-8436 .- 1471-2970. ; 372:1719
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Tidskriftsartikel (refereegranskat)abstract
- The harm that pathogens cause to hosts during infection, termed virulence, varies across species from negligible to a high likelihood of rapid death. Classic theory for the evolution of virulence is based on a trade-off between pathogen growth, transmission and host survival, which predicts that higher within-host growth causes increased transmission and higher virulence. However, using data from 61 human pathogens, we found the opposite correlation to the expected positive correlation between pathogen growth rate and virulence. We found that (i) slower growing pathogens are significantly more virulent than faster growing pathogens, (ii) inhaled pathogens and pathogens that infect via skin wounds are significantly more virulent than pathogens that are ingested, but (iii) there is no correlation between symptoms of infection that aid transmission (such as diarrhoea and coughing) and virulence. Overall, our results emphasize how virulence can be influenced by mechanistic life-history details, especially transmission mode, that determine how parasites infect and exploit their hosts.
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