Abstract 1521: High-fat diet-induced tumor promotion was abolished by blocking fatty acid oxidation in PDAC

Abstract Purpose: Obesity is well known to promote pancreatic ductal adenocarcinoma (PDAC) tumor development. However, the direct link between obesity and cancer has not been interpreted. We found that ATP production in cancer cells depends on fatty acid oxidation (FAO). Therefore, we propose blocking FAO in cancer may stop obesity from promoting PDAC growth. Experimental Design: To block FAO, SLC25A20 (carnitine-acylcarnitine carrier) was knocked down in human PDAC cells, which was implanted for xenograft in mice and treated with a high-fat diet (HFD, 60% fat) or no-fat diet (NFD, calorie-balanced 0% fat). To compare cancer development, survival rates, and histopathological differences were analyzed with KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) and KPC/Slc25a20+/- mice treated with regular diet (RD, 18% fat). Results: The median survival of KPC mice with HFD was decreased by 2.0 weeks compared to KPC mice with RD (regular diet). Xenografts of PDAC cells with HFD promoted tumor growth 2-fold compared to the xenograft with regular diet (RD). Xenograft with SLC25A20 knockdown PDAC cells in NFD reduced a 40-95% of tumor growth, and xenograft with SLC25A20 knockdown PDAC cells in HFD also resulted in a 65-95% reduction in tumor growth compared to controls. Conclusion: Blocking FAO reversed HFD-induced tumor growth promotion in pancreatic cancer. Cancer cells take advantage of HFD for ATP production by FAO. IGF or inflammation by HFD is no longer a direct mechanism to understand how HFD promotes tumor development. Funding source: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to SK (NRF-2019M3A9G1104345) and by a grant from the National Cancer Center of Korea to SHS (NCC 24H1210-2). Citation Format: Joon Hee Kang, Woojin Ham, Ho Lee, Wonyoung Choi, Jung Won Chun, Sang Myung Woo, Sung Hoon Sim, Soo-Youl Kim. High-fat diet-induced tumor promotion was abolished by blocking fatty acid oxidation in PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1521.