The Hippo signaling pathway is a highly conserved pathway involved in tissue development and regeneration that controls organ size through the regulation of cell proliferation and apoptosis. The core Hippo pathway is composed of a block of kinases, MST1/2 (Mammalian STE20-like protein kinase 1/2) and LATS1/2 (Large tumor suppressor 1/2), which inhibits nuclear translocation of YAP/TAZ (Yes-Associated Protein 1/Transcriptional co-activator with PDZ-binding motif) and its downstream association with the TEAD (TEA domain) family of transcription factors. This pathway was recently shown to be involved in tumorigenesis and metastasis in several cancers such as lung, breast, or colorectal cancers but is still poorly investigated in brain tumors. Gliomas are the most common and the most lethal primary brain tumors representing about 80% of malignant central nervous system neoplasms. Despite intensive clinical protocol, the prognosis for patients remains very poor due to systematic relapse and treatment failure. Growing evidence demonstrating the role of Hippo signaling in cancer biology and the lack of efficient treatments for malignant gliomas support the idea that this pathway could represent a potential target paving the way for alternative therapeutics. Based on recent advances in the Hippo pathway deciphering, the main goal of this review is to highlight the role of this pathway in gliomas by a state-of-the-art synthesis.

Glioblastoma (GBM) represents the most common and lethal primary malignant brain tumor. The standard treatment for glioblastoma patients involves surgical resection with concomitant radio and chemotherapy. Despite today's clinical protocol, the prognosis for patients remains very poor with a median survival of 15 months. Tumor resistance and recurrence is strongly correlated with a subpopulation of highly radioresistant and invasive cells termed Glioblastoma Stem Cells (GSCs). The transcription factor STAT3 has been found to be constitutively activated in different tumors including GBM and enhanced tumor radioresistance. In this study, we assessed radiosensitization of GSC lines isolated from patients by inhibition of STAT3 activation using Stattic or WP1066. We showed that inhibitor treatment before cell irradiation decreased the surviving fraction of GSCs suggesting that STAT3 inhibition could potentiate radiation effects. Finally, we investigated STAT3 activation status on 61 GBM clinical samples and found a preferential phosphorylation of STAT3 on Serine727 (pS727). Moreover, we found that pS727 was associated with a significant lower overall patient survival and progression-free survival but not pY705. Taken together, our results suggest that pS727-STAT3 could be a potential prognostic marker and could constitute a therapeutic target to sensitize highly radioresistant GSCs. www.impactjournals.com/oncotarget/