Characterization of FGFR signaling in prostate cancer stem cells and inhibition via TKI treatment.

Juyeon Ko,Martin Haas,Daniel J Donoghue,April N Meyer

doi:10.18632/oncotarget.27859

Juyeon Ko, Martin Haas + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.27859

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Journal: Oncotarget	Publication Date: Jan 5, 2021
Citations: 11	License type: cc-by

Affiliation: University of California, San Diego

Abstract

Metastatic castrate-resistant prostate cancer (CRPC) remains uncurable and novel therapies are needed to better treat patients. Aberrant Fibroblast Growth Factor Receptor (FGFR) signaling has been implicated in advanced prostate cancer (PCa), and FGFR1 is suggested to be a promising therapeutic target along with current androgen deprivation therapy. We established a novel in vitro 3D culture system to study endogenous FGFR signaling in a rare subpopulation of prostate cancer stem cells (CSCs) in the cell lines PC3, DU145, LNCaP, and the induced pluripotent iPS87 cell line. 3D-propagation of PCa cells generated spheroids with increased stemness markers ALDH7A1 and OCT4, while inhibition of FGFR signaling by BGJ398 or Dovitinib decreased cell survival and proliferation of 3D spheroids. The 3D spheroids exhibited altered expression of EMT markers associated with metastasis such as E-cadherin, vimentin and Snail, compared to 2D monolayer cells. TKI treatment did not result in significant changes of EMT markers, however, specific inhibition of FGFR signaling by BGJ398 showed more favorable molecular-level changes than treatment with the multi-RTK inhibitor Dovitinib. This study provides evidence for the first time that FGFR1 plays an essential role in the proliferation of PCa CSCs at a molecular and cellular level, and suggests that TKI targeting of FGFR signaling may be a promising strategy for AR-independent CRPC.

Highlights

Prostate cancer (PCa) is the fifth leading cause of cancer-related deaths among men worldwide [1]
We established a novel in vitro 3D culture system to study endogenous Fibroblast Growth Factor Receptor (FGFR) signaling in a rare subpopulation of prostate cancer stem cells (CSCs) in the cell lines PC3, DU145, LNCaP, and the induced pluripotent iPS87 cell line. 3D-propagation of PCa cells generated spheroids with increased stemness markers ALDH7A1 and OCT4, while inhibition of FGFR signaling by BGJ398 or Dovitinib decreased cell survival and proliferation of 3D spheroids
This study provides evidence for the first time that FGFR1 plays an essential role in the proliferation of PCa CSCs at a molecular and cellular level, and suggests that tyrosine kinase inhibitors (TKIs) targeting of FGFR signaling may be a promising strategy for AR-independent castrate-resistant prostate cancer (CRPC)

Summary

Introduction

Prostate cancer (PCa) is the fifth leading cause of cancer-related deaths among men worldwide [1]. While ADT is effective at initial stages, androgen-independent tumor cells eventually emerge and most patients relapse and develop metastatic castrateresistant prostate cancer (mCRPC) [3]. A rare subpopulation of cells exhibiting stem/progenitor properties are believed to be responsible for cancer recurrence, metastasis and chemoresistance [4,5,6,7]. These rare populations of cells are known as cancer stem cells (CSCs) or tumor-initiating cells for their ability to generate tumors in vivo with high efficiency. ALDH7A1 is a commonly used biomarker to identify CSCs in PCa [10]

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