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

• Published in: Nature communications Vol. 15; no. 1; pp. 8540 - 11
• Main Authors: de Laat, Vincent, Topal, Halit, Spotbeen, Xander, Talebi, Ali, Dehairs, Jonas, Idkowiak, Jakub, Vanderhoydonc, Frank, Ostyn, Tessa, Zhao, Peihua, Jacquemyn, Maarten, Wölk, Michele, Sablina, Anna, Augustyns, Koen, Vanden Berghe, Tom, Roskams, Tania, Daelemans, Dirk, Fedorova, Maria, Topal, Baki, Swinnen, Johannes V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.10.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/2; 14/63; 38/39; 38/91; 631/45/287/1187; 64/60; 692/4028/67/2327; 692/4028/67/327; 82/51; 82/58; Adenocarcinoma; Animals; Biology; Cancer; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell death; Cell Line, Tumor; Chemoresistance; Chemotherapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Deoxycytidine - therapeutic use; Drug Resistance, Neoplasm - genetics; Ferroptosis; Ferroptosis - drug effects; Gemcitabine; Humanities and Social Sciences; Humans; Lipid metabolism; Lipid Metabolism - drug effects; Lipid peroxidation; Lipid Peroxidation - drug effects; Lipids; MAP kinase; Metabolism; Mice; multidisciplinary; p38 Mitogen-Activated Protein Kinases - metabolism; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Peroxidation; Science; Science (multidisciplinary); Solid tumors; Temperature; Tumor cell lines; Tumor microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52978-z

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. The development of cancer is typically accompanied by changes in the tumor microenvironment that support tumor growth and affect therapy response. Here, the authors show that increased intratumoral temperature is an inherent feature of human pancreatic cancer and contributes to therapy resistance by altering the lipid content of the tumor.