Abstract 6562: Bro1 proteins govern a multivesicular bodies fate switch to regulate exosome secretion, metastasis and tumor immune evasion

Abstract Exosomes play pleiotropic tumor-promoting functions and are secreted by fusion of multivesicular bodies (MVBs) with the plasma membrane. However, MVBs are also directed to lysosomes for degradation and the mechanism controlling different fates of MVBs remains elusive. Here, we show that the pro-tumor protein WDR4 enhances exosome secretion through degrading the ESCRT-associated Bro1-family protein PTPN23. Mechanistically, PTPN23 and its paralog ALIX compete for binding to syntenin, thereby directing MVBs towards degradation and secretion, respectively. ALIX, but not PTPN23, recruits actin capping proteins CAPZA1/CAPZB to prevent branched F-actin accumulation around MVBs, thus enabling MVBs trafficking to cell periphery for secretion. Functionally, WDR4/ALIX dependent exosomes preferentially load a set of pro-tumor proteins to potentiate metastasis and immune evasion. Our study highlights a previously unprecedented coupling between biogenesis mechanism and fate decision of MVBs and its importance in exosome cargo landscape, which have potential broad impacts on boosting exosome production and devising cancer therapeutic strategy. Citation Format: Nai Yang Yeat, Li-Heng Liu, Yu-Hsuan Chang, Charles Pin-Kuang Lai, Ruey-Hwa Chen. Bro1 proteins govern a multivesicular bodies fate switch to regulate exosome secretion, metastasis and tumor immune evasion [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 6562.