Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer

Vincent de Laat, Halit Topal, Xander Spotbeen, Ali Talebi, Jonas Dehairs, Jakub Idkowiak, Frank Vanderhoydonc, Tessa Ostyn, Peihua Zhao, Maarten Jacquemyn, Michele Wölk, Anna Sablina, Koen Augustyns, Tom Vanden Berghe, Tania Roskams, Dirk Daelemans, Maria Fedorova, Baki Topal and Johannes V. Swinnen ()
Additional contact information
Vincent de Laat: KU Leuven and Leuven Cancer Institute (LKI)
Halit Topal: University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI)
Xander Spotbeen: KU Leuven and Leuven Cancer Institute (LKI)
Ali Talebi: KU Leuven and Leuven Cancer Institute (LKI)
Jonas Dehairs: KU Leuven and Leuven Cancer Institute (LKI)
Jakub Idkowiak: KU Leuven and Leuven Cancer Institute (LKI)
Frank Vanderhoydonc: KU Leuven and Leuven Cancer Institute (LKI)
Tessa Ostyn: University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI)
Peihua Zhao: VIB-KU Leuven Center for Cancer Biology
Maarten Jacquemyn: KU Leuven Department of Microbiology and Immunology
Michele Wölk: Faculty of Medicine Carl Gustav Carus of TU Dresden
Anna Sablina: VIB-KU Leuven Center for Cancer Biology
Koen Augustyns: University of Antwerp
Tom Vanden Berghe: VIB-UGent Center for Inflammation Research
Tania Roskams: University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI)
Dirk Daelemans: KU Leuven Department of Microbiology and Immunology
Maria Fedorova: Faculty of Medicine Carl Gustav Carus of TU Dresden
Baki Topal: University Hospitals Leuven, KU Leuven and Leuven Cancer Institute (LKI)
Johannes V. Swinnen: KU Leuven and Leuven Cancer Institute (LKI)

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52978-z

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