Obesity-mediated extracellular vesicle secretion as a targetable driver of endometrial cancer initiation and progression

Introduction: Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, with obesity accounting for approximately 57% of cases. The molecular mechanisms linking obesity to EC initiation remain poorly defined. Emerging evidence suggests that obesity enhances extracellular vesicle (EV) secretion and alters EV-associated oncogenic signaling. This study investigates obesity-mediated EV dysregulation in adipose, uterine, and EC tissues and explores its role in early EC pathogenesis, biomarker development, and therapeutic intervention. Methods: Endometrial hyperplasia and EC were induced in immunocompetent mice using high-fat diets (HFD; 45% or 60% kcal fat) for 25 weeks. Molecular profiling was conducted using LC-MS/MS. EV concentration and size were quantified by nanoparticle tracking analysis (NTA) and visualized by transmission electron microscopy (TEM). Expression of TMEM205, STAT5, FAS, and the tumor suppressor PIAS3 was assessed by immunohistochemistry, ELISA, and RT-PCR in tissues from HFD-treated mice and obese EC patients. Additional studies evaluated EV-mediated tumor progression and treatment response in xenograft models receiving chemotherapy or immunotherapy. Results: Obese EC patient samples exhibited significantly increased EV secretion and upregulation of oncogenic proteins in adipose and uterine tissues compared to non-obese controls. In HFD-treated mice, elevated body weight, abdominal adiposity, uterine horn enlargement, and chronic inflammation correlated with endometrial hyperplasia and EC initiation. These phenotypes were associated with increased EV secretion, upregulation of TMEM205, FAS, and STAT5, and marked downregulation of PIAS3. HFD-induced EVs carried oncogenic proteins linked to elevated serum glucose and lipid levels and altered immune profiles. EVs from obese conditions also promoted aggressive EC progression and resistance to chemotherapy and immunotherapy. Treatment with the small-molecule EV secretion inhibitor DAP-5 significantly reduced body weight, adipose accumulation, and EV output in HFD-fed mice and restored normal uterine morphology while suppressing EV-associated oncogenic signaling. Conclusion: Obesity-mediated EV secretion is a major driver of EC initiation and progression. Targeting EV biogenesis represents a promising preventive and therapeutic strategy for obesity-associated EC. These preclinical findings provide a strong rationale for advancing EV-targeted interventions, including first-in-human trials aimed at preventing obesity-driven EC development.