Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, with obesity contributing to 57% of cases. This study delves into the molecular mechanisms of extracellular vesicle (EV) release, which carry oncogenic proteins, and examines their role in obesity-related EC. Understanding these pathways is essential for uncovering how obesity promotes EC and for developing novel preventive and therapeutic strategies. Our findings revealed a pronounced increase in EV secretion containing TMEM205, STAT5, and FAS in adipose and uterine tissues and serum from obese EC patients compared to non-cancer controls. We also detected changes in EV regulatory proteins—Rab7, Rab11, and Rab27a—in tissues and serum from obesity-associated EC cases. In a 24-week high-fat diet (HFD, 45% kcal) mouse model, we observed higher body weight, increased fat deposition, enlarged uterine horns, and greater inflammation in HFD-fed mice. These changes correlated with elevated EV release, increased levels of TMEM205, FAS, and STAT5, and reduced PIAS3 expression in adipose and uterine tissues. Additionally, adipocyte-derived EV enhanced EC cell proliferation, migration, and tumor growth in xenografts. Treatment with HO-3867 or Metformin decreased EV release in vitro and in vivo, suppressed high glucose- or adipocyte-stimulated EC cell proliferation, and reduced body weight and fat accumulation in HFD mice. These treatments also prevented HFD-induced hyperplasia by modulating EV-regulated proteins and lowering oncogenic protein expression. Overall, this work provides mechanistic insight into obesity-driven EV release with oncogenic cargo in EC and supports further exploration of EV-targeted strategies to prevent obesity-mediated EC.
