EDNRB‐dependent endothelin signaling reduces proliferation and promotes proneural‐to‐mesenchymal transition in gliomas

Diffuse gliomas are primary brain tumors including glioblastomas (GB), astrocytomas, and oligodendrogliomas, the latter two harboring IDH1 mutations and exhibiting slower progression. Gliomas display cellular plasticity, with transitions between astrocyte‐like, oligodendrocyte‐like, progenitor‐like, and mesenchymal‐like states driven by genetic alterations and microenvironmental signals. The proneural‐to‐mesenchymal transition (PMT), associated with increased malignancy, is tightly regulated by the tumor microenvironment, notably through cytokine signaling and non‐tumor cell interactions. Endothelins (ET‐1, ET‐2, ET‐3), vasoactive peptides mainly produced by vascular cells, signal through the G‐protein‐coupled receptors EDNRA and EDNRB and were previously suggested to promote glioma proliferation based on serum‐based models. Here, we revisited endothelin signaling using eleven serum‐free glioma lines and tumor samples. Multi‐omics and electrophysiological analyses identified EDNRB as the predominant receptor, enriched in astrocyte‐like cells, increased by BMPs or growth factor withdrawal, and repressed by interferons, IL‐6 family cytokines, endothelins, and Hippo/YAP signaling. EDNRA was confined to a perivascular tumor subpopulation and induced by Notch signaling selectively in GB. Functionally, endothelins reduced proliferation while promoting migration and PMT via EDNRB‐dependent Ca 2+ signaling, ERK/STAT3 activation, and apamin‐sensitive SK2/SK3 potassium channel activity. Collectively these findings establish endothelin signaling as an important regulator of glioma cell plasticity and behavior.