Abstract B048: Targeting PPARG to block obesity-associated pancreatic cancer progression

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is the 3rd leading cause of cancer-related death in the United States and one of the few cancers for which incidence is increasing. This trend in increased incidence has been attributed in part to obesity. Obesity is associated with increased risk of pancreatic cancer and advanced disease stage in patients, concordant with rodent studies showing that obesity accelerates tumorigenesis and metastasis. Although studies have largely focused on the role of inflammation in obesity-associated pancreatic cancer, the cancer cell-autonomous mechanisms by which lipid availability in obesity impacts tumorigenesis remain quite poorly understood. Given the abundant evidence for dysregulated lipid metabolism in tumors, I hypothesized that cancer cells are primed to exploit exogenous lipids in obesity, accelerating disease progression. By mapping lipid-protein interactions in tumor and metastasis-enriched RNA-seq networks, I identified the nuclear hormone receptor PPARG as a potential mediator of obesity-associated lipid signaling in pancreatic cancer. PPARG is an attractive prospective mediator of obesity-associated PDA progression because it is a metabolic regulator activated by a broad set of lipid ligands, suggesting a dual role in lipid sensing and metabolic control. PPARG is also positioned at an interesting junction in PDA etiology; PPARG agonists are used to treat diabetes (a PDA risk factor) and have previously been studied for anti-cancer effects. However, PPARG agonists have seen little clinical success in and recent work has suggested that their use may even increase bladder cancer risk. PPARG is overexpressed in pancreatic tumors where it is associated with poor prognosis, further casting doubt on its anti-tumorigenic function. In my own studies, I found that PPARG agonists had no effect on tumor viability, while the PPARG antagonist T0070907 reduced organoid viability in vitro. Modeling the convergent effects of PPARG and obesity, I supplemented organoids with a mixture of lipids in the presence of PPARG antagonist and found that lipids boosted the viability of both tumor and metastatic organoids dependent on PPARG activity in vitro. These results suggest that PPARG can mediate the pro-tumorigenic function of exogenous lipids. As the incidence of both obesity and pancreatic cancer continue to rise, defining the role of PPARG in PDA could have significant implications for the development of new strategies to treat or prevent obesity-associated cancer. Citation Format: L. Paige Ferguson. Targeting PPARG to block obesity-associated pancreatic cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B048.