Abstract 2967: Bone voyage: FGFR1, stemness, and the Wnt trail to prostate cancer metastasis

Abstract Prostate cancer (PCa) lethality largely stems from the progression to castration-resistant PCa (CRPC) bone metastasis. We previously reported that fibroblast growth factor receptor 1 (FGFR1) is overexpressed in a subset of human CRPC bone metastases, and that FGFR1 overexpression of both α and β isoforms drives bone metastases and reduces survival in experimental metastatic murine models with intracardiac PCa cells injection, posing its blockade as a promising therapeutic strategy for advanced PCa. An on-going clinical study at our department at MD Anderson is currently evaluating erdafitinib, an FGFR inhibitor, for treating men with CRPC bone metastases (ClinicalTrials.gov Identifier: NCT04754425). However, the dynamics behind FGFR-driven PCa progression remain elusive. As FGFR signaling has previously been linked to the development and proliferation of PCa stem-cells, we hypothesized that FGFR promotes PCa bone metastasis by modulating cell plasticity. In vitro assays confirmed that FGFR1α- and FGFRβ-expressing PCa cells exhibited increased colony formation and confluency, and a more stem-like phenotype, evidenced by altered morphology, smaller cell size, elevated aldehyde dehydrogenase (ALDH) levels, and enhanced tumorsphere formation (p<0.0001). Consistently, RNA-seq analysis of PCa cells and MDA PCa patient-derived xenografts (PDX) showed a significantly positive correlation between FGFR1 levels and stem-cell markers (p<0.05). Furthermore, PCa patients from TCGA-PRAD (497 primary PCa) and SU2C (81 metastatic CRPC) datasets with enrichment of FGFR-correlated stem-cell categories exhibited increased risk of progression (log-rank p<0.05). Among the stem-categories that correlate with FGFR expression, genes from Wnt signaling, a pathway involved in stem-cell traits regulation and implicated in PCa, emerged prominently (FERMT2, FZD7, NES, CORO1C, BMP4, MEF2C, GJA1, SFRP1, WNT2B, CDH2). Bioinformatics analysis also revealed significant correlation between TCF/LEF factors and FGFR1 in TCGA-PRAD patients. FGFR1-expressing PCa cells showed increased TCF reporter activity, indicating Wnt activation, and nuclear β-catenin immunostaining in FGFR1-expressing PDXs and human CRPC bone metastases further confirmed this activation. Overall, our findings suggest that FGFR1 drives PCa progression through Wnt signaling-induced stemness, conferring cancer cells the plasticity to adapt to the bone microenvironment. Future studies aim to further characterize the FGFR1-induced stemness and dedifferentiation mechanisms underlying PCa bone dissemination and evaluate FGFR-targeted therapies. Citation Format: Agustina Sabater, Pablo Sanchis, Nicolas Anselmino, Juan Bizzotto, Jun Yang, Jiabin Dong, Peter D. Shepherd, Paul G. Corn, Elba Vazquez, Christopher J. Logothetis, Nora Navone, Geraldine Gueron, Estefania Labanca. Bone voyage: FGFR1, stemness, and the Wnt trail to prostate cancer metastasis [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 2967.