Abstract 4325: FXYD5 plays diverse roles in immune evasion and tumor progression in prostate cancer

Abstract FXYD5 is involved in various biological processes, including inflammation, tumor progression, drug resistance, and hypertension. It has been suggested as a potential biomarker for several cancers, with elevated levels found in ovarian and colon cancer. However, the role of FXYD5 in prostate cancer has not yet been elucidated. Here, we found that the FXYD5 was expressed in tumor cells by sc-RNA sequencing of human metastatic prostate tumor tissues. The expression levels of FXYD5 were higher in androgen receptor (AR)-negative prostate cancer cells compared to AR-positive prostate cancer cells. Intrinsically, FXYD5 knockout promoted PC3 cell proliferation, migration, and invasion. In vivo studies showed that FXYD5 knockout promoted PC3 tumor growth, while overexpression of FXYD5 inhibited PC3 tumor progression. However, in AR-positive 22Rv1 cells, overexpression of FXYD5 promoted tumor progression. In vitro assays indicate that overexpression of FXYD5 in PC3, C42B, and 22Rv1 cells reduces mitochondrial membrane potential and reactive oxygen species. Additionally, FXYD5 overexpression reduces lactate dehydrogenase activity and lactate levels in PC3 cells but has no effect on these parameters in 22Rv1 cells. In PC3 cells, FXYD5 overexpression promotes the formation of tight cell-cell interactions, accompanied by downregulation of membrane markers and nuclear enlargement. In contrast, these effects are not observed in 22Rv1 or C42B cells. Further, FXYD5 is identified as a potential Siglec-7 ligand by CRISPRi screen. FXYD5 knockout decreased Siglec-7 Fc binding capacity and enhanced the NK-cell mediated cytotoxicity in prostate cancer cells. In a humanized mouse model, 22Rv1 tumor growth was inhibited with human immune cell modulation. However, when FXYD5 was overexpressed in 22Rv1 cells, tumor growth was not impacted by immune cell-based therapy. This was due to the interaction of FXYD5 on cancer cells with Siglec-7 on immune cells, thereby inducing immunosuppressive signals. These findings suggest potential therapeutic strategies targeting FXYD5-based mechanisms. Citation Format: Ru Wen, G Edward W. Marti, Neeladrisingha Das, Zhengyuan Qiu, Nathan Lam, Eric E. Peterson, Zenghua Fan, Aram Lyu, Fernando Jose Garcia Marques, Abel Bermudez, Hongjuan Zhao, Lawrence Fong, Guillem Pratx, Donna M. Peehl, Sharon J. Pitteri, James D. Brooks. FXYD5 plays diverse roles in immune evasion and tumor progression in prostate cancer [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 4325.