Abstract 1035: Western lifestyle leads to obesity and cancer via a common factor FTO

Abstract FTO, the first identified RNA N6-methyladenosine (m6A) demethylase, has been reported by our group to play an oncogenic role in acute myeloid leukemia (AML) and by others in various solid tumors, including colorectal and liver cancers. Additionally, FTO was the first gene identified through genome-wide association studies (GWAS) to be associated with obesity risk, with evidence linking elevated FTO expression to increased food intake and obesity development. While obesity is a recognized risk factor for cancer, whether FTO serves as a shared factor driving both obesity and cancer remains unclear. To address this knowledge gap, we employed in vivo mouse models with Fto expression manipulated through genetic knockout or pharmacological inhibition to investigate its respective roles in tumorigenesis and obesity. In an ENU-treated spontaneous tumor model, we confirmed that Fto-WT mice showed greater susceptibility to tumorigenesis than Fto-KO mice. When fed a Western diet high in sugar and fat, Fto-KO mice exhibited resistance to diet-induced obesity compared to Fto-WT mice. Similar protective effects against diet-induced obesity were observed in models treated with CS1, a potent small-molecule FTO inhibitor developed by our group. To explore the interplay between obesity and cancer, we established combined obesity-tumor models. Western diet-fed obese mice were either treated with ENU to induce spontaneous tumors or transplanted with MC-38 cells. In both scenarios, CS1 treatment simultaneously reduced obesity and tumorigenesis significantly. Mechanistically, FTO inhibition partially reversed Western diet-induced alterations in immune cell populations, indicating an immune-modulatory role for FTO in the pathogenesis of obesity and cancer. Together, our findings identify FTO as a common factor in the development of obesity and tumor and highlight the potential of targeting FTO for the simultaneous prevention and intervention of these conditions. Citation Format: Dong Wu, Ying Qing, Keith Leung, Meiling Chen, Zhicong Zhao, Yangchan Li, Li Han, Wei Li, Zhenhua Chen, Chao Shen, Yuan Che, Tingting Tang, Kitty Wang, Lillian Sau, Zhaoxu Xu, Xiaolan Deng, Jianjun Chen. Western lifestyle leads to obesity and cancer via a common factor FTO [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 1035.