EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells

Benjamin Krusche, Cristina Ottone, Melanie P. Clements, Ewan R. Johnstone, Katrin Goetsch, Huang Lieven, Silvia G. Mota, Poonam Singh, Sanjay Khadayate, Azhaar Ashraf, Timothy Davies, Steven M. Pollard, Vincenzo De Paola, Federico Roncaroli, Jorge Martinez-Torrecuadrada, Paul Bertone, Simona Parrinello

Research output: Contribution to journalArticlepeer-review

Abstract

Glioblastomas (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.

Original languageEnglish
Article numbere14845
JournaleLife
Volume5
DOIs
Publication statusPublished - 28 Jun 2016

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