Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer
A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.
Authors
- Maria Fedorova (ORCID: https://orcid.org/0000-0002-4692-3885)
- Jonas Dehairs (ORCID: https://orcid.org/0000-0002-6789-2264)
- Koen Augustyns (ORCID: https://orcid.org/0000-0002-5203-4339)
- Johannes V. Swinnen (ORCID: https://orcid.org/0000-0002-7720-5077)
- Anna Sablina (ORCID: https://orcid.org/0000-0001-9526-4014)
- Xander Spotbeen (ORCID: https://orcid.org/0000-0002-1510-967X)
- Vincent de Laat (ORCID: https://orcid.org/0000-0003-0252-1179)
- Frank Vanderhoydonc
- Peihua Zhao (ORCID: https://orcid.org/0009-0007-7272-3274)
- Baki Topal (ORCID: https://orcid.org/0000-0002-2687-7535)
- Maarten Jacquemyn (ORCID: https://orcid.org/0000-0003-2626-4189)
- Tessa Ostyn
- Tania Roskams (ORCID: https://orcid.org/0000-0002-2816-1530)
- Jakub Idkowiak (ORCID: https://orcid.org/0000-0002-4336-9006)
- Dirk Daelemans (ORCID: https://orcid.org/0000-0001-7092-1153)
- Michele Wölk (ORCID: https://orcid.org/0000-0001-5558-4582)
- Halit Topal
- Ali Talebi (ORCID: https://orcid.org/0000-0003-2601-2686)
- Tom Vanden Berghe (ORCID: https://orcid.org/0000-0002-1633-0974)
Institutions
- University of Antwerp (BE)
- Rega Institute for Medical Research (BE)
- VIB-KU Leuven Center for Cancer Biology (BE)
- VIB-UGent Center for Inflammation Research (BE)
- University Hospital Carl Gustav Carus (DE)
- Technische Universität Dresden (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-02
- DOI
- https://doi.org/10.1038/s41467-024-52978-z
- Citations
- 16
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 6.70
Funders
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Fonds Wetenschappelijk Onderzoek
- Stichting Tegen Kanker
- Sächsisches Staatsministerium für Wissenschaft und Kunst
- Sächsische Aufbaubank
- Kom op tegen Kanker
- Vlaamse regering
- Fondation contre le Cancer