ETV2 mediates endothelial transdifferentiation of glioblastoma

• DOI: 10.1038/s41392-018-0007-8
• Publication Date: 2018-02-07T11:56:56Z
• Authors: Chengjian Zhao; Gustavo A. Gomez; Yuwei Zhao; Yu Yang; Dan Cao; Jing Lu; Hanshuo Yang; Shuo Lin
• Keywords: 0301 basic medicine; 03 medical and health sciences; Article; 3. Good health

AbstractGlioblastoma 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 (endo-transdifferentiation). 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 anti-angiogenesis 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.