Krusche, BenjaminOttone, CristinaClements, Melanie PJohnstone, Ewan RGoetsch, KatrinLieven, HuangMota, Silvia GSingh, PoonamKhadayate, SanjayAshraf, AzhaarDavies, TimothyPollard, Steven MDe Paola, VincenzoRoncaroli, FedericoMartinez Torrecuadrada, Jorge LuisBertone, PaulParrinello, Simona2019-07-112019-07-112016-06-28Elife. 2016;5. pii: e14845.2050-084Xhttp://hdl.handle.net/20.500.12105/7888Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/Eph/ephrinGBMCancer biologyCancer stem cellsCell biologyHumanNousePerivascular invasionAnimalsEphrin-B2GlioblastomaHeterograftsHumansIntravital MicroscopyMiceNeoplastic Stem CellsCell MovementCell ProliferationAtribución-NoComercial-CompartirIgual 4.0 Internacional27350048510.7554/eLife.148452050-084XeLifeopen access