Abstract 6544: Effects of lipid metabolism on therapy-resistant prostate cancer cell-derived extracellular vesicle function in the tumor microenvironment

Abstract Background: The chemotherapeutic agent docetaxel is a gold standard treatment for advanced, metastatic prostate cancer. However, the development of docetaxel resistance is a challenge to the effective management of the disease. Fatty acid synthase (FASN) is a central enzyme involved in lipid biosynthesis, a process linked to a therapy resistant phenotypes an immunosuppressive microenvironment. We hypothesize that FASN-driven lipogenesis alters prostate cancer cell-derived extracellular vesicle function within the tumor microenvironment. In particular, we will test whether extracellular vesicles from highly lipogenic docetaxel-resistant prostate cancer cells promote alternative macrophage activation. Methods: Using cell-based models of docetaxel resistance (including both androgen receptor [AR]-positive and AR-negative lines), we first tested whether exposure of U937-derived macrophages to prostate cancer cells influenced the frequency of M1(CD86) or M2 (CD163) marker expression by immunocytochemistry. Next, we isolated extracellular vesicles from chemosensitive and chemoresistant prostate cancer cells and performed Western blots to detect FASN. Ongoing studies are evaluating the role of extracellular vesicles from prostate cancer cells, compared to vesicle-free cultured medium, on macrophage polarization by immunocytochemistry and/or flow cytometry. To assess the clinical relevance and prognostic utility of FASN/macrophage polarization overlap, we performed multiplex immunohistochemistry using human prostate cancer tissue microarrays. FASN and M1 (CD86) and M2 (CD163) macrophage markers were detected and quantified using a Keyence fluorescent microscope. Results: Our data indicate that FASN is detectable in extracellular vesicles from prostate cancer cells and that the co-expression of FASN with a high M1-to-M2 ratio of macrophage markers in human prostate tumors correlates with aggressive disease based on clinicopathological variables. Conclusions: These findings suggest that FASN may play a significant role beyond the confines of prostate cancer cells, extending to the tumor immune system and possibly to other cell types in the tumor microenvironment. Further work is needed to define the mechanism and intracellular impact of tumoral FASN uptake by tumor-associated macrophages. Acknowledgements: Funding was provided by the Puerto Rico Science, Research and Technology Trust through the Catalyzer Research Grant mechanism to C.J.D.O. during his tenure at the Ponce Research Institute, Ponce, Puerto Rico. Citation Format: Carolina Restrepo Soto, Katherine Carrero Figueroa, Carlos Joel Diaz Osterman. Effects of lipid metabolism on therapy-resistant prostate cancer cell-derived extracellular vesicle function in the tumor microenvironment [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 6544.