Abstract PO-025: Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress
Authors: Han Xu , Burrows Michelle , Simon Celeste , Jiang Yanqing , Keith Brian 
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a 5-year survival rate of only 10%. Nearly 95% of PDAC harbor oncogenic KRAS, which has been largely “undruggable” in the past. One hallmark of PDAC tumor microenvironment is dense desmoplasia, as a result of abnormal accumulation of extracellular matrix and proliferative fibroblasts. During tumorigenesis, pancreatic stellate cells (PSCs) become activated to a myofibroblast-like phenotype and contribute to the fibrotic environment of PDAC. Desmoplasia-induced hypovascularity severely limits the delivery of oxygen and nutrients. Our laboratory revealed that hypoxia is prominent even at the pancreatic intraepithelial neoplasia (PanIN) stage, which is the dominant precursor lesion of PDAC. Hypoxia inhibits oxygen-dependent processes in cancer metabolism, such as unsaturated lipid biosynthesis which requires oxygen as the terminal electron acceptor. Hypoxia also stimulates exogenous lipid uptake. Previous publications demonstrated that RAS-transformed cells preferentially take up unsaturated lysophosphatidylcholines (LPCs) from culture media. However, under limited nutrient conditions, in the desmoplastic environment, the potential lipid source is not well understood. Interestingly, a lipidomic study of a PSC secretome displayed a significant elevation of LPCs, suggesting that PSCs are the potential lipid source in the PDAC microenvironment. Our data indicate that exogenous unsaturated fatty acids sustain PDAC cell viability under hypoxia and nutrient deficiency. We also 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 are not experiencing hypoxic stress as much as malignant epithelium cells in vivo by analyzing single-cell RNA-seq data and IHC, which suggests the capability of cancer-associated fibroblasts in providing unsaturated lipids to PDAC cells. Based on our lipidomic mass spectra of PSC conditioned medium, we identify that LPCs are actively imported by PDAC cells and prove that unsaturated LPCs maintain PDAC cell survival under nutritional stress. Our overall hypothesis is that activated PSCs support PDAC cell survival by providing unsaturated lipids, particularly LPCs, and inhibition of unsaturated lipid uptake through impeding lipid transporter activity or LPC synthesis by PSCs could potentially induce PDAC cell death under metabolically challenging conditions. We will hinder possible pathways responsible for LPC uptake in PDAC cells and generate in vivo models to achieve therapeutic benefits of PDAC. In summary, our research aims to demonstrate the metabolic crosstalk between PSCs and PDAC cells under stress conditions. The key advance of this study is that activated PSCs suppress PDAC cell death by supplying tumor cells with unsaturated LPCs for maintaining lipid homeostasis, in a hypoxic and nutrient-poor environment. Our findings will reveal a novel metabolic target for developing combinatorial therapy of PDAC.

Citation Format: Xu Han, Michelle Burrows, Celeste Simon, Yanqing Jiang, Brian Keith. Investigating lipid homeostasis in pancreatic ductal adenocarcinoma under tumor-like stress [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-025.