Abstract 6167: Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth

Abstract

Abstract Both the cell-intrinsic metabolic network and the uniquely altered cell-extrinsic tumor microenvironment dictate tumor metabolism. However, while much is known about how cell-intrinsic factors regulate tumor metabolism, the effects of cell-extrinsic factors remain poorly understood. In particular, despite evidence that tumor nutrient availability extrinsically regulates tumor metabolism, further investigation has been hindered by the lack of models to study physiological nutrient availability in vitro.To accurately model the tumor nutrient microenvironment, our group quantified nutrient availability in pancreatic ductal adenocarcinoma (PDAC) tumor perfusate and created a medium to mimic this in vitro, called tumor interstitial fluid medium (TIFM). We compare the effects of TIFM-culture to maintenance in conventional culture medium (RPMI-1640) as a control for standard laboratory conditions. Using this model, I found that TIFM-cultured PDAC cells downregulate lipid synthesis, making TIFM-cultured cells uniquely reliant upon extracellular lipid uptake for growth. Analysis of murine PDAC tumors confirms downregulated lipogenesis in vivo, suggesting cell-extrinsic nutrients render lipogenesis dispensable—and lipid uptake necessary—for PDAC tumor growth. Notably, this contrasts studies in conventional culture media that claim lipogenesis is critical for PDAC growth.I am currently working to: (1) understand how the nutrient microenvironment alters lipid metabolism and (2) determine the extracellular lipids and transporters pancreatic cancer cells require for growth. Regarding the first question, transcriptomic analysis of TIFM-cultured cells revealed significant deactivation of SREBPs, master regulators of intracellular lipid and sterol synthesis, suggesting cell-extrinsic nutrient cues suppress lipogenesis by altering SREBP signaling. I am currently investigating which TIFM nutrients alter this signaling. I am also performing lipidomics analysis and lipid transporter knockdown experiments to identify lipids and transporters that TIFM-cultured cells require for growth. Collectively, these experiments will clarify the role extracellular nutrients play in driving changes to PDAC lipid metabolism and may suggest novel therapeutic treatment options for PDAC patients. Citation Format: Patrick Jonker, Alexander Muir. Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6167.