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

TitleEphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsKrusche B, Ottone C, Clements MP, Johnstone ER, Goetsch K, Lieven H, Mota SG, Singh P, Khadayate S, Ashraf A, Davies T, Pollard SM, De Paola V, Roncaroli F, Martinez-Torrecuadrada J, Bertone P, Parrinello S
JournalElife
Volume5
Date Published2016 Jun 28
ISSN2050-084X
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.

DOI10.7554/eLife.14845
Alternate JournalElife
PubMed ID27350048
PubMed Central IDPMC4924994
Grant ListMC_PC_12009 / / Medical Research Council / United Kingdom
MC_U120088464 / / Medical Research Council / United Kingdom
MC_UP_A652_1002 / / Medical Research Council / United Kingdom
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