ETV2 mediates endothelial transdifferentiation of glioblastoma

Glioblastoma multiforme (GBM) is characterized by extensive endothelial hyperplasia. Recent studies suggest that a subpopulation of endothelial cells originates via vasculogenesis by the transdifferentiation of GBM tumor cells into endothelial cells (endotransdifferentiation). The molecular mechanism underlying this process remains poorly defined. Here, we show that the expression of ETS variant 2 (ETV2), a master regulator of endothelial cell development, is highly correlated with malignancy. Functional studies demonstrate that ETV2 is sufficient and necessary for the transdifferentiation of a subpopulation of CD133+/Nestin+GBM/neural stem cells to an endothelial lineage. Combinational studies of ChIP-Seq with gain-of-function RNA-Seq data sets suggest that ETV2, in addition to activating vascular genes, represses proneural genes to direct endo-transdifferentiation. Since endo- transdifferentiation by ETV2 is VEGF-A independent, it likely accounts for the observed resistance of GBM tumor cells to antiangiogenesis therapy. Further characterization of the regulatory networks mediated by ETV2 in endo-transdifferentiation of GBM tumor cells should lead to the identification of more effective therapeutic targets for GBM.