FGF-trapping hampers cancer stem-like cells in uveal melanoma

Abstract

Purpose : Cancer stem-like cells (CSCs) are a subpopulation of tumor cells responsible for tumor initiation, metastasis, chemoresistance, and relapse. Recently, CSCs have been identified in uveal melanoma (UM), the most common primary intraocular tumor in adults. UM is highly resistant to systemic chemotherapy and effective therapies are eagerly required. The Fibroblast Growth Factor (FGF) system has been implicated in tumor progression, as well as in regulation and survival of CSCs in several human cancers. On this premise, we investigated the effect of the FGF-trap NSC12 on UM progression, focusing on the UM-CSC subpopulation.

Methods : The effect of FGF-trapping on UM cell proliferation and vitality was evaluated by FACS analysis. NSC12 was exploited to single out the UM-CSC subset; then, gene expression and signaling activation were assessed by qRT-PCR and Western Blotting, respectively. Aldehyde dehydrogenase (ALDH) activity was analyzed by FACS. Melanosphere formation was evaluated under non-adherent conditions. In vivo experiments were performed by tumor engraftment on chick embryo chorioallantoic membrane (CAM). Hierarchical clustering of gene expression was performed on data publicly available on The Cancer Genome Atlas (TCGA).

Results : Treatment of 92.1, Mel270, and Mel285 UM cells with NSC12 significantly impaired cell proliferation. Notably, FGF-trapping strongly affected the survival of the CSC ALDH^br population. Accordingly, pre-treatment with NSC12 significantly hampered the melanosphere formation capacity of UM cells (Fig. 1A). In this frame, by inhibiting the FGF/FGF receptor (FGFR) system we isolated an FGF-sensitive UM population characterized by stem-like properties. Furthermore, FGF-trapping deeply affected UM-CSC survival in vivo. At the clinical level, hierarchical clustering of TCGA gene expression data revealed a strong correlation between FGFs/FGFRs and stemness-associated genes, allowing the identification of three distinct clusters of patients characterized by different clinical outcomes (Fig. 1B).

Conclusions : Our findings support the evidence that the FGF/FGFR signaling is an essential regulator of cancer stemness in UM tumors, pointing to anti-FGF drugs as a novel therapeutic strategy to strike the UM-CSC component.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

 

Fig. 1: A) Effect of NSC12 on UM cells. *p≤0.05, **p<0.01 vs control, Student’s t Test. B) Hierarchical clustering of gene expression data of 80 UM samples and patient disease-free survival curves.