FGFR1/FOXM1 pathway: a key regulator of glioblastoma stem cells radioresistance and a prognosis biomarker.

ABSTRACT

Glioblastoma are known to be aggressive and therapy-resistant tumors, due to the presence of glioblastoma stem cells inside this heterogeneous tumor. We investigate here the involvement of FGFR1 in glioblastoma stem-like cells (GSLC) radioresistance mechanisms. We first demonstrated that the survival after irradiation was significantly diminished in FGFR1-silenced (FGFR1-) GSLC compared to control GSLC. The transcriptome analysis of GSLCs FGFR1(-) showed that FOX family members are differentially regulated by FGFR1 inhibition, particularly with an upregulation of FOXN3 and a downregulation of FOXM1. GSLC survival after irradiation was significantly increased after FOXN3 silencing and decreased after FOXM1 inhibition, showing opposite effects of FGFR1/FOX family members on cell response to ionizing radiation. Silencing FGFR1 or FOXM1 downregulated genes involved in mesenchymal transition such as GLI2, TWIST1, and ZEB1 in glioblastoma stem-like cells. It also dramatically reduced GSLC migration. Databases analysis confirmed that the combined expression of FGFR1/FOXM1/MELK/GLI2/ZEB1/TWIST1 is significantly associated with patients overall survival after chemo-radiotherapy treatment. All these results, associated with our previous conduced ones with differentiated cells, clearly established that FGFR1-FOXM1 dependent glioblastoma stem-like cells radioresistance pathway is a central actor of GBM treatment resistance and a key target to inhibit in the aim to increase the sensitivity of GBM to the radiotherapy.