Krusche, B;
Ottone, C;
clements, MP;
Johnstone, ER;
Goetsch, K;
Lieven, H;
Mota, SG;
... Parrinello, S; + view all
(2016)
EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells.
eLife
, 5
, Article e14845. 10.7554/eLife.14845.
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EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells.pdf - Published Version Available under License : See the attached licence file. Download (9MB) | Preview |
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 ephrinB2 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.
| Type: | Article |
|---|---|
| Title: | EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.7554/eLife.14845 |
| Publisher version: | http://dx.doi.org/10.7554/eLife.14845 |
| Language: | English |
| Additional information: | Copyright © 2016 Krusche et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10050137 |
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