Ephrin-B2 is a glioblastoma oncogene that drives perivascular invasion and proliferation

Abstract

Glioblastoma multiforme (GBM) are the most aggressive and devastating tumours of the brain and are essentially incurable. They are defined by diffuse invasion of the surrounding brain parenchyma along preexisting structures like the vasculature. Glioma stem cells (GSC) are thought to be largely responsible for tumour recurrence following treatment due to their high resistance to therapy, their ability to recapitulate tumours from single cells and their marked invasive potential. Here we show, that normal neural stem cell in the subventricular zone are compartmentalised by endothelial ephrinB2 and their proliferation limited through activation of p53 in an Eph signalling dependent manner. GSCs however evade both compartmentalisation and proliferation inhibition and are able to invade perivascularly. Intravital imaging, coupled with mechanistic studies in vitro revealed that upregulation of ephrinB2 in highly aggressive, mesenchymal GSCs enables escape from endothelial compartmentalisation through homotypic forward signalling. Surprisingly we also find that that ephrinB2 reverse signalling promotes tumourigenesis by mediating anchorage-independent cytokinesis through activation of RhoA. In preclinical models using human GSCs we show, that inhibition of ephrinB2 by RNA silencing or with ephrinB2-blocking antibodies strongly suppresses tumourigenesis of established glioblastoma by inducing cell-cycle arrest and blocking GBM/vascular interactions. Thus, ephrinB2 is an oncogene and represents an attractive candidate for anti-GBM therapies aimed at eradicating the GSC compartment by targeting both glioma invasion and proliferation.