Author ORCID Identifier

0000-0003-3201-7790

Date of Graduation

12-2019

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Nora M. Navone

Committee Member

Pierre D. McCrea

Committee Member

Anil K. Sood

Committee Member

Juan Fueyo

Committee Member

Fen Wang

Abstract

The fibroblast growth factor receptor (FGFR) 1 is implicated in prostate cancer (PCa) progression. Various FGFR1 isoforms have been described and we demonstrate here that the well-characterized FGFR1 a and b isoforms are correlated with the expression of different genes and pathways in human PCa. Direct injection of PC3 PCa cells overexpressing FGFR1 isoforms into the femur of mice resulted in enhanced tumor growth and reduction in bone volume when compared with PC3 expressing empty vector. However, only PC3 overexpressing FGFR1 b was associated with increased osteoclast parameters, suggesting that each isoform may mediate diverse biological effects (similar findings were obtained when using C4-2B PCa cell line). Also, PC3 PCa cells overexpressing FGFR1 a injected intracardially significantly reduced mouse survival (P = 0.0001) and PCa cells overexpressing FGFR1 a and b increased the incidence of bone metastases (P = 0.00005 and P = 0.025 compared to controls). Accordingly, immunohistochemical analysis of castration-resistant human PCa bone metastases revealed a significant enrichment of FGFR1 expression compared with treatment-naïve, non-metastatic primary tumors (P = 0.0007). Importantly, we demonstrate by RPPA analysis that FGFR1 induces expression of the anchoring filament protein ladinin 1 (LAD1) in PC3 cells. Furthermore, LAD1 gene amplification and LAD1 expression were significantly enriched in castration-resistant human PCa bone metastases (P < 0.0001 and P = 0.0048 respectively) suggesting that LAD1 is implicated in FGFR1-mediated metastases.

In summary, our studies indicate that FGFR1 drives the PCa metastatic phenotype, thus further supporting the development of FGFR blockade as a therapy for metastatic PCa. Our results also suggest that new FGFR1 signatures define pathway activation and this knowledge will help identify markers of pathway inhibition in human PCa. Finally, our findings implicate, for the first time, LAD1 in the metastatic phenotype of a subpopulation of men with PCa.

Keywords

prostate cancer, bone metastasis, FGFR1, LAD1, ladinin 1

Available for download on Friday, November 13, 2020

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