Abstract 3377: Exploring the role of obesity-induced exosome secretion and associated proteins in endometrial cancer pathogenesis: A roadmap for prevention through exosome inhibition
Authors: Sakaue Takahiko , Dorayappan Kalpana Deepa Priya , Zingarelli Roman , Khadraoui Wafa , Anbalagan Muralidharan , Wallbillich John , Wascovich Mark , Paramita Pragyan , Suarez Adrian , Cosgrove Casey , Maxwell Larry G. , Koga Hironori , O’Malley David , Cohn David , Karuppaiyah Selvendiran 
Published: March 2024

Abstract
Introduction: Endometrial cancer (EC) is the leading gynecologic malignancy in the U.S., with obesity implicated in 57% of cases. This study explores the molecular workings of oncogenic protein expression (TMEM205, STAT5, and FAS) and their role in regulating exosome secretion. Understanding these mechanisms is crucial for unraveling pathways involved in obesity-related EC, informing the development of innovative strategies for prevention and treatment.
Methods: The isolated exosomes were quantified using nanoparticle tracking analyzer (NTA) and their size measured by Transmission electron microscopy (TEM). TMEM205, STAT5, FAS and PIAS3 expression was confirmed by IHC, ELISA and RT-PCR in patient and high fat diet treated mouse tissue. Endometrial hyperplasia was developed in immunocompetent mice using high fat diet (HFD; 45 kcal% fat diet) for 16 weeks.
Results: Our study investigates exosome secretion and the regulation of oncogenic proteins in adipose and uterine tissues from obese EC patients compared to non-obese EC samples. Analyzing the effects of a 45% kcal high-fat diet (HFD) on mice over 24 weeks, we observed higher body weight and increased adipose tissue in the HFD group, along with enlarged uterine horns and heightened inflammation. This correlated with elevated exosome secretion and increased expression of TMEM205, FAS and STAT5, while the tumor suppressor gene PIAS3 was downregulated. The identified small molecule inhibitor, DAP-5, selectively targeting TMEM205 and exosome secretion, demonstrated a significant reduction in body weight and adipose tissue accumulation when administered to HFD mice. Additionally, DAP-5 treatment restored normal uterine morphology and reduced the expression of exosome-related proteins.
Conclusion: This study offers central insights into the mechanisms underlying obesity-mediated TMEM205 expression and exosome secretion, shedding light on their role in the pathogenesis of EC. Additionally, it provides pre-clinical evidence supporting the initiation of the first in-human studies for exosome-targeted therapies aimed at preventing obesity-mediated EC.
Citation Format: Takahiko Sakaue, Kalpana Deepa Priya Dorayappan, Roman Zingarelli, Wafa Khadraoui, Muralidharan Anbalagan, John Wallbillich, Mark Wascovich, Pragyan Paramita, Adrian Suarez, Casey Cosgrove, Larry G. Maxwell, Hironori Koga, David O’Malley, David Cohn, Selvendiran Karuppaiyah. Exploring the role of obesity-induced exosome secretion and associated proteins in endometrial cancer pathogenesis: A roadmap for prevention through exosome inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3377.