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

// Valerie Gouaze-Andersson 1 , Marie-Julie Gherardi 1 , Anthony Lemarie 1 , Julia Gilhodes 2 , Vincent Lubrano 3 , Florent Arnauduc 1 , Elizabeth Cohen-Jonathan Moyal 1, 2, * and Christine Toulas 1, 2, * 1 Institut National de la Sante et de la Recherche Medicale (INSERM) UMR1037/Universite Toulouse III Paul Sabatier, Cancer Research Center of Toulouse (CRCT), Toulouse, F-31000, France 2 Institut Claudius Regaud, IUCT-O, Toulouse, F-31059, France 3 CHU PURPAN-Pavillon Baudot, Place du Dr Baylac, Toulouse-Cedex 3, 31024, France * These authors contributed equally to this work Correspondence to: Valerie Gouaze-Andersson, email: valerie.gouaze-andersson@inserm.fr , gouaze@hotmail.com Keywords: FGFR1; FOX; glioblastoma; radioresistance; prognosis biomarker Received: April 28, 2018      Accepted: July 13, 2018      Published: August 03, 2018 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.