Glioblastomas (GBMs) are highly vascularized cancers. Transdifferentiation of GBM stem-like cells (GSCs) into GSC-derived endothelial cells (GdECs) contributes to GBM neovascularization. To dissect the molecular mechanisms and the signaling pathways underlying GSC contribution to tumor vascularization, we identified a three miRNA signature able to discriminate GSCs from GdECs by regulating different signaling pathways. DUSP8 resulted as the common target of the miRNA signature identified and is negatively regulated by miR-1825. DUSP8 is emerging as a critical negative regulator MAPKs pathway and is involved in cell oxidative stress response and apoptosis, as well as, in several diseases, including cancer. In GBM patients, DUSP8 and miR-1825 expression are inversely correlated and DUSP8 down-regulation is significantly associated with higher microvascular density and poor overall survival. Exploring the impact of DUSP8 in GSC transdifferentiation, we demonstrated that DUSP8 down-regulation interferes with MAPK pathway and affects soluble factor release. In vitro DUSP8 modulation experiments showed that DUSP8 enforced expression impairs GdEC ability to form tube-like structures. Gene expression variations induced by DUSP8 modulation affect transcripts associated with EMT pathway, confirming that DUSP8 shutdown and, therefore, the activation of MAPK pathway, is mandatory to GSC transdifferentiation. In vivo experiments demonstrated that both DUSP8 enforced expression and silencing dramatically affect gliomagenesis. Dissecting the molecular mechanisms underlying the contribution of GSCs to tumor angiogenesis might represent a chance to develop new and more efficient antiangiogenic therapeutic protocols for GBM treatment. Our findings provide a strong rationale to develop therapeutic strategies based on modulation of DUSP8 for GBM treatment.