Abstract PR024: Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress
Authors: Han Xu , Burrows Michelle , Jiang Yanqing , Mesaros Clementina , Schultz David , Keith Brian , Simon Celeste 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival rate of only 10%. One hallmark of PDAC’s tumor microenvironment is dense desmoplasia, due to abnormal accumulation of extracellular matrix and proliferative fibroblasts. During tumorigenesis, pancreatic stellate cells (PSCs) obtain myofibroblast-like signatures and contribute to the fibrotic environment of PDAC. Desmoplasia-induced hypovascularity severely limits oxygen and nutrient delivery. Our laboratory revealed that hypoxia is prominent even at the pancreatic intraepithelial neoplasia (PanIN) stage, a dominant precursor lesion of PDAC. Hypoxia inhibits oxygen-dependent metabolic processes. For example, unsaturated lipid biosynthesis relies on oxygen to maintain desaturase enzymatic activities. Hypoxia also stimulates lipid uptake. Previous studies demonstrated that RAS-transformed cells preferentially import unsaturated lysophosphatidylcholines (LPCs) from culture media. However, in a nutrient-limited fibrotic environment, the potential source of lipids is unclear. Interestingly, a lipidomic study of a PSC secretome displayed a significant amount of LPCs, suggesting that PSCs are the potential lipid source in the PDAC microenvironment. Our data indicate that exogenous unsaturated lipids sustain PDAC cell viability under hypoxia and nutrient deficiency. Moreover, we find PDAC cell survival under tumor-like stress is enhanced in PSC conditioned medium, but not in delipidated conditioned medium. Strikingly, we show that cancer-associated fibroblasts do not experience hypoxic stress as much as adjacent malignant epithelium cells in vivo, suggesting cancer-associated fibroblasts provide unsaturated (and other) lipids to PDAC cells. Based on our lipidomic mass spectra of PSC conditioned medium, we determined that LPCs are actively utilized by PDAC cells for phosphatidylcholine and triglyceride regeneration. To discover novel therapeutic strategies, we performed small molecule screens to identify potential drugs that disrupt LPC uptake and metabolism by PDAC cells. Our overall hypothesis is that activated PSCs (and potentially other fibroblasts) support PDAC cell survival by providing lipids, particularly LPCs, and inhibition of LPC utilization by cancer cells or unsaturated lipid synthesis by PSCs induces PDAC cell death under metabolically challenging conditions. In summary, this project aims to demonstrate metabolic crosstalk between fibroblasts and PDAC cells under stress conditions. The key advance of my research is that activated PSCs suppress PDAC cell death by supplying tumor cells with unsaturated LPCs for the maintenance of lipid homeostasis, in a hypoxic and nutrient-poor environment. If true, our findings will reveal novel metabolic targets for developing combinatorial therapy of PDAC.
Citation Format: Xu Han, Michelle Burrows, Yanqing Jiang, Clementina Mesaros, David Schultz, Brian Keith, Celeste Simon. Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress [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 PR024.