Abstract 3738: Triangulating the metabolic crossroads: understanding the complex interplay between metabolic dysregulation and obesity cancer risk

Abstract Obesity is on the verge of surpassing tobacco use as the leading modifiable cause of cancer in the U.S., contributing to over 40,000 new cancer cases annually. With obesity rates rising, especially in younger populations, its association with increased cancer risk is becoming more evident. There is an urgent need to understand the mechanisms underlying the relationship between obesity related metabolic dysregulation and cancer risk, including factors that may mitigate health disparities. Recent advances in molecular oncology and metabolic research provide opportunities in understanding the intricate connections between metabolic dysregulation, obesity, and cancer. This session will describe a novel triangulation approach, synthesizing evidence from randomized controlled trials, mechanistic animal studies, and large-scale secondary data analyses to build a comprehensive understanding of these relationships from the NCI-sponsored Metabolic Dysregulation and Obesity Cancer Risk Consortium (MeDOC). MeDOC is guided by team science and transdisciplinary approach to advance our understanding of the underlying mechanisms that connect obesity, metabolic dysregulation, and cancer risk to identify markers that will enhance cancer risk prediction and identify targets for intervention. Both obesity and metabolic dysregulation contribute to a cascade of derangements in adipocyte function, growth factors, inflammation, gut microbiome, immune function, sex hormones, lipid and glucose metabolism which, in turn, can disrupt several downstream signaling pathways related to cancer initiation and progression. These derangements occur systemically and within the tumor microenvironment itself. Through 5 individual projects and 6 collaborative projects in human and animal studies, we are currently evaluating the role of A-FABP (adipocyte fatty acid binding protein), ceramides, inflammation, gut mediated metabolites, gut microbiome dysbiosis in cancers of the colon, breast, and liver, facilitated by the coordinating center. Methodological triangulation will be emphasized throughout, demonstrating how randomized trials provide causal inference, animal studies reveal mechanistic insights, and secondary data analyses establish population-level patterns and clinical relevance. Experts from the MeDOC Consortium will review current understanding, describe the ongoing human and animal studies and big data analytic methods to establish robust causal frameworks. Open discussion will include our early career members to engage the community to identify emerging areas. Chairperson: Marinella Temprosa Hallmarks of metabolic dysregulation and their role in obesity cancer risk: Bing Li Harmonization of Animal Studies: Liza Makowski Design of Randomized and Observational Studies: James Hebert Transdisciplinary Collaboration Discussion: Neli Ulrich Citation Format: Marinella Temprosa, Bing Li, Liza Makowski, James Hebert, Cornelia Ulrich. Triangulating the metabolic crossroads: understanding the complex interplay between metabolic dysregulation and obesity cancer risk [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 3738.