Increased Expression and Altered Cellular Localization of Fibroblast Growth Factor Receptor-Like 1 (FGFRL1) Are Associated with Prostate Cancer Progression.

Abstract

Simple SummaryProstate cancer (PCa) is one of the most frequently diagnosed malignancies in men. PCa is primarily regulated by androgens, but other mechanisms, such as fibroblast growth factor receptor (FGFR) signaling, are also involved. In some patients, PCa relapses after surgical removal of prostate, and androgen deprivation therapy (ADT) is used as the first-line treatment. Unfortunately, the patients often lose response to ADT and progress by other mechanisms to castration-resistant, currently non-curable PCa. In our study, we aimed to identify better diagnostic markers and therapeutic targets against PCa. We analyzed patient PCa tissue samples from radical prostatectomies and biopsies, and used physiologically relevant 3D organoids and mouse xenografts to study FGFR signaling in PCa. We found that FGFRL1, a protein belonging to the FGFR family, plays a role in PCa. Our results suggest that FGFRL1 has significant effects on PCa progression and has potential as a prognostic biomarker.Fibroblast growth factor receptors (FGFRs) 1–4 are involved in prostate cancer (PCa) regulation, but the role of FGFR-like 1 (FGFRL1) in PCa is unclear. FGFRL1 expression was studied by qRT-PCR and immunohistochemistry of patient tissue microarrays (TMAs) and correlated with clinical patient data. The effects of FGFRL1 knockdown (KD) in PC3M were studied in in vitro culture models and in mouse xenograft tumors. Our results showed that FGFRL1 was significantly upregulated in PCa. The level of membranous FGFRL1 was negatively associated with high Gleason scores (GSs) and Ki67, while increased cytoplasmic and nuclear FGFRL1 showed a positive correlation. Cox regression analysis indicated that nuclear FGFRL1 was an independent prognostic marker for biochemical recurrence after radical prostatectomy. Functional studies indicated that FGFRL1-KD in PC3M cells increases FGFR signaling, whereas FGFRL1 overexpression attenuates it, supporting decoy receptor actions of membrane-localized FGFRL1. In accordance with clinical data, FGFRL1-KD markedly suppressed PC3M xenograft growth. Transcriptomics of FGFRL1-KD cells and xenografts revealed major changes in genes regulating differentiation, ECM turnover, and tumor–stromal interactions associated with decreased growth in FGFRL1-KD xenografts. Our results suggest that FGFRL1 upregulation and altered cellular compartmentalization contribute to PCa progression. The nuclear FGFRL1 could serve as a prognostic marker for PCa patients.