FGFR1 Expression and Role in Migration in Low and High Grade Pediatric Gliomas.

Katherine Karakoula,Susan C. Short,Naomi Egbivwie,Filomena Esteves,Matthew Humphries,Tracy Warr,Anke Brüning-Richardson,Azzam Ismail,Julia V. Cockle,Claire Taylor,Ruth Morton

doi:10.3389/fonc.2019.00103

Abstract

The heterogeneous and invasive nature of pediatric gliomas poses significant treatment challenges, highlighting the importance of identifying novel chemotherapeutic targets. Recently, recurrent Fibroblast growth factor receptor 1 (FGFR1) mutations in pediatric gliomas have been reported. Here, we explored the clinical relevance of FGFR1 expression, cell migration in low and high grade pediatric gliomas and the role of FGFR1 in cell migration/invasion as a potential chemotherapeutic target. A high density tissue microarray (TMA) was used to investigate associations between FGFR1 and activated phosphorylated FGFR1 (pFGFR1) expression and various clinicopathologic parameters. Expression of FGFR1 and pFGFR1 were measured by immunofluorescence and by immunohistochemistry (IHC) in 3D spheroids in five rare patient-derived pediatric low-grade glioma (pLGG) and two established high-grade glioma (pHGG) cell lines. Two-dimensional (2D) and three-dimensional (3D) migration assays were performed for migration and inhibitor studies with three FGFR1 inhibitors. High FGFR1 expression was associated with age, malignancy, tumor location and tumor grade among astrocytomas. Membranous pFGFR1 was associated with malignancy and tumor grade. All glioma cell lines exhibited varying levels of FGFR1 and pFGFR1 expression and migratory phenotypes. There were significant anti-migratory effects on the pHGG cell lines with inhibitor treatment and anti-migratory or pro-migratory responses to FGFR1 inhibition in the pLGGs. Our findings support further research to target FGFR1 signaling in pediatric gliomas.

Highlights

Pediatric and adult gliomas are recognized to be distinct disease entities
Our findings support a role for fibroblast growth factor receptor 1 (FGFR1) signaling in pediatric glioma migration with a potential for kinase signaling targeting: our tissue microarray (TMA) studies indicated an association of FGFR1 expression and malignancy and tumor grade; membranous phosphorylated FGFR1 (pFGFR1) localization was associated with malignancy and grade
We found evidence of an association of activated FGFR1 when localized in the cell membrane with malignancy and tumor grade (2 and 3)

Summary

Introduction

Pediatric and adult gliomas are recognized to be distinct disease entities. current standard of care for adult and pediatric high grade glioma (HGG) remains the same and both are associated with dismal disease outcome. Pediatric and adult gliomas are clearly distinct biologically, with differences in location, transformation rate [from low grade gliomas (LGG) to HGGs] and differences in tumor biology and genetic drivers [1]. Becker et al reported that 6.7% of pilocytic tumors had FGFR1 point mutations on Lys656 and subsequently that tumors carrying the mutation had significantly poorer prognoses compared to wild-type variants [9] These studies support exploring FGFR1 as a potential genetic driver in pediatric glioma tumorigenesis [7, 8] and as a druggable target. Our findings support a role for FGFR1 signaling in pediatric glioma migration with a potential for kinase signaling targeting: our TMA studies indicated an association of FGFR1 expression and malignancy and tumor grade; membranous pFGFR1 localization was associated with malignancy and grade. As all cell lines were FGFR1 wildtype we propose that FGFR1 amplification alone may contribute to disease progression

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