Abstract C080: Biosocial disparities drive glycoxidation to induce adipocyte differentiation in the prostate tumor microenvironment

Abstract Background: Advanced glycation end-products (AGEs) are pro-inflammatory metabolites formed through non-enzymatic glycoxidation, a reaction accelerated by aging, hyperglycemia, poor diet, and physical inactivity. AGEs accumulate in cells and tissues to drive metabolic dysfunction, oxidative stress, and chronic inflammation. Prostate cancer (PCa), a leading cause of cancer death in men, is influenced by metabolic dysfunction and marked disparities in outcomes. These studies assessed if as a consequence of biosocial synergy between social, environmental, and biological drivers of health, AGE accumulation is accelerated and modulates adipose–tumor metabolic crosstalk to promote PCa malignancy. Methods: Relationships between AGE accumulation and biosocial synergy are epitomized by nutritional behavior. To recapitulate this experimentally, male C3-TAg transgenic mice were fed either a regular diet or a high-AGE diet for 8 weeks. Tumors were harvested and immunohistochemistry and adipocyte morphology were analyzed. For in vitro experiments, 3T3-L1 preadipocytes were differentiated in the presence or absence of AGE-modified bovine serum albumin (BSA-AGE - 25 μg/mL) for 12 days, and lipid accumulation was visualized at days 5, 9, and 12 using BioTracker™ 488 Lipid Droplet stain. Paracrine effects were evaluated in MYC-CaP cells co-cultured with WPMY1 fibroblasts in Transwell systems treated with BSA-AGE for 24 hours. Western blotting on preadipocytes and mature 3T3-L1 adipocytes (day 12) assessed p-ACLY, RAGE, FABP4, and FABP5 expression. RNA sequencing and targeted metabolomics of AGE-fed and control tumors were integrated through conjoint KEGG enrichment to identify overlapping pathways Results: The results showed that dietary AGE intake increased AGE buildup in PPAT, crown-like structures near PIN lesions, and reduced adipocyte size. AGE-treated 3T3-L1 cells showed early lipid accumulation but reduced total content and more micro-droplets by day 12. Co-cultured MYC-CaP cells exhibited enhanced lipid uptake. Western blotting showed upregulation of p-ACLY, RAGE, FABP4, and FABP5. Gene ontology analysis of RNA-seq data revealed significant enrichment of mitochondrial energy-related processes, including oxidative phosphorylation (p = 1.5 × 10-8), ATP synthesis-coupled electron transport (p = 6.5 × 10-8), and respiratory chain complex assembly (p = 1.6 × 10-7). Targeted metabolomics detected 10 significantly altered (fold change ≥ 2, p < 0.05) metabolites. Conjoint transcriptomic–metabolomic analysis identified oxidative phosphorylation (p < 0.01) as a diet-responsive metabolic pathway, suggesting that AGE-driven lipolysis fuels mitochondrial metabolism in prostate cancer cells. Conclusion: Dietary AGEs promote adipocyte lipolysis and potentially fatty acid release, enhancing oxidative phosphorylation in prostate tumors. These findings establish a mechanistic link between AGE-driven adipose dysfunction as a consequence of social, environmental, and biological drivers that impact tumor metabolism to represent a potential therapeutic vulnerability. Citation Format: Fariha Imtiaz, Boxiao Ding, Tuong Vi V. Nguyen, Bradley A. Krisanits, Gamze Bulut, Bhoomika Kaur, Can E. Senkal, Sarah Spiegel, Nolan Wages, Victoria J. Findlay, David P. Turner. Biosocial disparities drive glycoxidation to induce adipocyte differentiation in the prostate tumor microenvironment [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr C080.