Abstract 3327: Obesity-mediated extracellular vesicle secretion: A potential target for preventing endometrial hyperplasia and cancer initiation
Authors: Lakshmi Narasimhan Chakrapani, Kalpana Deepa Priya Doraiyappan, Ganesh Yadagiri, Jessica Velasquez, Shyam Sundaram, Takahiko Sakaue, Casey Cosgrove, George Larry Maxwell, David M. O'Malley, David E. Cohn, Selvendiran Karuppaiyah
Journal: Cancer Research (2025)

Abstract Introduction: Endometrial cancer (EC) is the most common gynecologic malignancy in the U.S., with obesity contributing to 57% of cases. This study investigates the molecular mechanisms linking obesity to EC, focusing on extracellular vesicle (EV) secretion and oncogenic protein regulation in adipose and uterine tissues. Understanding these pathways could lead to innovative preventive and therapeutic strategies for obesity-related EC. Methods: Endometrial hyperplasia and cancer were induced in immunocompetent mice using high-fat diets (HFD; 45% or 60% kcal from fat) for 25 weeks. Molecular profiling was performed using LC-MS/MS, while EV quantification and size analysis were conducted via nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM), respectively. The expression of TMEM205, STAT5, FAS, and PIAS3 was assessed using immunohistochemistry (IHC), ELISA, and RT-PCR in patient and HFD-treated mouse adipose and uterine tissues. Results: EV secretion and the regulation of oncogenic proteins were significantly elevated in adipose and uterine tissues from obese EC patients compared to non-obese controls. In mice fed a 45% or 60% kcal HFD for 25 weeks, we observed increased body weight, abdominal adipose tissue, uterine horn enlargement, and heightened inflammation, correlating with endometrial hyperplasia and cancer initiation. This was associated with increased EV secretion, upregulated TMEM205, FAS, and STAT5 expression, and downregulation of the tumor suppressor PIAS3. Furthermore, HFD-induced EV secretion carrying oncogenic proteins were linked to elevated serum glucose, lipid and Free fatty acid levels. A small-molecule inhibitor, DAP-5, selectively targeting EV secretion, significantly reduced body weight and adipose tissue accumulation in HFD-treated mice. DAP-5 treatment also restored normal uterine morphology and reduced the expression of EV-related oncogenic proteins. Conclusion: This study highlights obesity-mediated EV secretion as a key contributor to the pathogenesis of EC and identifies it as a potential target for prevention. Preclinical findings support further investigation into EV-targeted therapies, including initiating first-in-human trials to prevent obesity-driven EC. Citation Format: Lakshmi Narasimhan Chakrapani, Kalpana Deepa Priya Doraiyappan, Ganesh Yadagiri, Jessica Velasquez, Shyam Sundaram, Takahiko Sakaue, Casey Cosgrove, George Larry Maxwell, David M. O'Malley, David E. Cohn, Selvendiran Karuppaiyah. Obesity-mediated extracellular vesicle secretion: A potential target for preventing endometrial hyperplasia and cancer initiation [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 3327.