Investigating lipogenesis mediated resistance to cytotoxic therapy in PDAC

Pancreatic ductal adenocarcinoma is notoriously resistant to chemotherapy and radiation therapy (RT). Lipid metabolism has been implicated in tumor cell intrinsic resistance to oxidative stress by protecting against ferroptosis, as well as cell extrinsic immunosuppression. Genes of de novo lipid production through lipogenesis are upregulated in many cancers including PDAC. This project proposes to characterize de novo tumor lipid production following cytotoxic therapy, as a means of escaping cell intrinsic cell death by evasion of ferroptosis, and immune mediated cell killing by promoting M2 macrophage polarization. We propose to test whether genetic and pharmacologic inhibition of lipogenesis alters the cellular and microenvironmental lipid makeup, and whether this alteration enhances the sensitivity to oxidative stress through ferroptosis, and immune evasion by ApoE mediated suppressive macrophage polarization. We believe this could represent a novel mechanism of therapeutic resistance that could be targeted with inhibitors of lipogenesis in combination with cytotoxic therapies already in clinical use. We propose to use in vitro and in vivo tumor studies, utilizing mass spectrometry, RNA seq, and flow cytometry to characterize the effects of cytotoxic therapy and inhibitors of lipogenesis on lipid makeup, immune infiltration and polarization, and tumor sensitivity to oxidative stress. Aim 1: Determine the impact of PDAC lipogenesis on tumor resistance to oxidative stress and cytotoxic therapy. We hypothesize that oncogenic KRAS upregulates lipogenesis proteins ACC and FASN in PDAC cells through SREBP1, leading to increased lipid turnover and ability to resist oxidative stress induced ferroptosis, driving therapeutic resistance. We will characterize the changes PDAC cellular lipid expression following oxidative stress by RT by mass spectrometry, and determine if inhibition of lipogenesis and Lands cycle abrogates these changes. We will then test if pharmacologic inhibition of lipogenesis and Lands cycle can sensitize PDAC cells to RT. Aim 2: Demonstrate the effect of PDAC lipogenesis on tumor ApoE expression, macrophage polarization and immune mediated therapeutic resistance to cytotoxic therapy in vivo. We hypothesize that RT increases PDAC lipid production and lipid oxidation by stimulating expression of SREBP1, leading to tumor immune suppression through ApoE secretion and M2 polarization, preventing anti-tumor immunity and immune clearance in the presence of cytotoxic therapy. We intend to test whether genetic and pharmacologic inhibition of lipogenesis lipid makeup of the tumor microenvironment after RT, altering ApoE expression and tumor macrophage polarization, and resistance to RT. Project Number: 1R21CA302996-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Adam Mueller | Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH, PITTSBURGH, PA | Award Amount: $408,829 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CTH-V (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11363958