Endothelins influences the proliferation-migration balance of IDH1-mutant glioma cells and promotes proneural to mesenchymal transition [RNAseq-275HCMEC]

Adult diffuse gliomas are the deadliest brain tumours including IDH-wildtype glioblastomas of worst prognosis and diffuse low grade IDH-mutant astrocytomas and oligodendrogliomas. These glial tumours display distinct tumoral cell population defeating current therapies. Our group has unveiled the role of NOTCH signalling in glioblastoma cell plasticity and in the conversion of oligodendrocytic-like to astrocytic-like tumoral cells in IDH-mutant low-grade gliomas which escalate inevitably to higher grade malignant gliomas. To gain insight into signalling pathways regulating glioma cell plasticity and malignancy, we focused our work on endothelin signalling including endothelin peptide ligands (ET-1, ET-2, ET-3) binding to G-protein coupled endothelin receptors A and B (EDNRA, EDNRB). Here, using glioma patient samples and glioma patient-derived cell lines, we showed that endothelin reduces glioma cell proliferation while increasing migration initiating a proneural to mesenchymal transition. Mechanistically, EDNRB activation led to IP3-dependent calcium mobilization, apamin-sensitive KCNN2/KCNN3 potassium currents and phosphorylation of ERK1/2 and STAT3 in glioma cells. Finally, we studied endothelin receptor regulation by tumoral microenvironment stimuli highlighting a role for EDNRA induced by NOTCH and hypoxia in perivascular hypoxic area in glioblastoma. Altogether, this study demonstrates endothelin signalling as a key player in mesenchymal transformation of diffuse IDH-mutant gliomas and glioblastomas.