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Abstract
Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) trigger distinct endothelial responses involving either angiogenic or circumferential vascular growth (vasectasia). The latter process is selectively triggered by mesenchymal (but not proneural) GSCs and is mediated by a subset of extracellular vesicles (EVs) able to transfer EGFR/EGFRvIII transcript to endothelial cells. Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs.
Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.
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1 The Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada (GRID:grid.63984.30) (ISNI:0000 0000 9064 4811)
2 McGill University, Department of Biochemistry, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Rosalind & Morris Goodman Cancer Institute, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
3 McGill University, Department of Human Genetics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)
4 Dalhousie University, Department of Pathology & Laboratory Medicine, Halifax, Canada (GRID:grid.55602.34) (ISNI:0000 0004 1936 8200)
5 Hokuto Social Medical Corporation, Hokuto Hospital, Department of Neurosurgery, Obihiro, Japan (GRID:grid.452447.4) (ISNI:0000 0004 0595 9093)
6 The Research Institute of the McGill University Health Centre, McGill University, Montreal, Canada (GRID:grid.63984.30) (ISNI:0000 0000 9064 4811); McGill University, Department of Biochemistry, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649); McGill University, Department of Human Genetics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649)