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Tumor growth is inevitably accompanied by changes in the tumor-microenvironment to which cancer cells have to adapt in order to thrive. Alterations in metabolism and blood perfusion of solid tumors have been suggested to drive a spontaneous increase in tumoral temperature. However, it is currently unknown if this phenomenon affects cancer biology. We found increased temperature in human pancreatic ductal adenocarcinoma (PDAC) tumors. By mimicking this observation in PDAC cell lines, we found that cancer cells adapt to tumoral temperature by altering the cellular lipidome and accordingly evade ferroptosis, a lipid-dependent form of cell death. We found evidence that tumoral temperature-induced ferroptosis evasion depends on p38-MAPK deactivation and ultimately drives resistance to the chemotherapeutic drug gemcitabine. Collectively, our findings suggest a direct role for p38-dependend ferroptosis evasion in gemcitabine resistance, and we identify tumoral temperature as a pathophysiological driver of this process. Our discovery unveils temperature as an unexplored hallmark of the tumor-microenvironment. Citation Format: Vincent de Laat, Halit Topal, Jonas Dehairs, Xander Spotbeen, Ali Talebi, Frank Vanderhoydonc, Tessa Ostyn, Tania Roskams, Baki Topal, Johan Swinnen. Evidence for a tumoral temperature driven chemoresistance pathway in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C077.

Membranes are unique phospholipid (PL) interfaces that play a central role in cancer cell biology. However, PL composition of clinical tumors, and its dynamic regulation, remains a critical gap in the molecular profiling of this disease. Here, we used mass spectrometry-based spatial imaging and lipidomics to generate PL profiles of clinical prostate tissues upon cancer development and in patient-derived tumor explants (PDEs; n=43) cultured with the current clinical agent enzalutamide. Analysis of more than 100 PL species in tumors and matched normal tissues from 21 patients revealed a complexity of cancer-related changes in the tissue PL landscape. Phosphatidylcholine (PC)-based PLs were the most abundant PL class, and their relative abundance was increased in tumors compared to matched benign tissues. A greater proportion of monounsaturated fatty acid chains was characteristic of PLs in tumors, most evident in the PC and phosphatidylethanolamine (PE) PLs, as was striking elongation of fatty acid chains in the phosphatidylinositol (PI) and phosphatidylserine (PS) classes. The abundance of specific PL species and saturation groups was significantly associated with malignancy in both this and an independent cohort of unmatched patient tissues (n=47). Notably, the PL profile was significantly associated with the ERG molecular subtype and basal proliferative index (Ki67) in tumors. Furthermore, we identified individual PL species that were associated with the antiproliferative response to enzalutamide, in cultured PDEs. In light of these PL features, we proposed acetyl coA carboxylase (ACC) as a novel therapeutic target in prostate cancer. Indeed, blocking lipid biosynthesis and elongation in prostate tumors with an ACC inhibitor (ACCi, PF-05175157) significantly reduced tumor cell proliferation in PDE tissues (n=13), concomitant with increased pACC1 staining and a decreased proportion of longer chain PLs. Our findings suggest that the clinical PCa lipidome is not only a marker of malignant transformation and aggressiveness, but also therapeutic response to enzalutamide. Moreover, defining this unique biology identified further clinically actionable targets that may improve prostate cancer outcomes. Citation Format: Lisa M. Butler, Chui Yan Mah, Jonas Dehairs, Andrew Vincent, Shadrack Mutuku, Xander Spotbeen, Rajdeep Das, Zeyad Nassar, Luke Selth, Paul Trim, Marten Snel, David Lynn, Lisa Horvath, Wayne Tilley, Margaret Centenera, Johannes Swinnen. Phospholipid profiling of clinical prostate tissues reveals targetable alterations in membrane lipid composition accompanying tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2076.