title: EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells.
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.
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krusche
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Cristina
authors.initials: C
authors.lastname: Ottone
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Clements
authors.affiliation: Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.|European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom.
authors.forename: Ewan R
authors.identifier: 0000-0002-6656-6088
authors.initials: ER
authors.lastname: Johnstone
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Katrin
authors.initials: K
authors.lastname: Goetsch
authors.affiliation: Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.|Neuroplasticity and Diseases Group, MRC Clinical Sciences, London, United Kingdom.
authors.forename: Huang
authors.initials: H
authors.lastname: Lieven
authors.affiliation: Proteomics Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Mota
authors.affiliation: Department of Histopathology, Imperial College Healthcare Trust, London, United Kingdom.
authors.forename: Poonam
authors.initials: P
authors.lastname: Singh
authors.affiliation: Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Khadayate
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Azhaar
authors.initials: A
authors.lastname: Ashraf
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Davies
authors.affiliation: MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
authors.affiliation: Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.|Neuroplasticity and Diseases Group, MRC Clinical Sciences, London, United Kingdom.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Paola
authors.affiliation: Department of Histopathology, Imperial College Healthcare Trust, London, United Kingdom.|Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom.
authors.forename: Federico
authors.initials: F
authors.lastname: Roncaroli
authors.affiliation: Proteomics Unit, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Martinez-Torrecuadrada
authors.affiliation: Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.|European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Bertone
authors.affiliation: Cell Interactions and Cancer Group, MRC Clinical Sciences Centre (CSC), London, United Kingdom.|Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Simona
authors.identifier: 0000-0003-0820-6292
authors.initials: S
authors.lastname: Parrinello
mesh_terms: D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D036388:Ephrin-B2 / Q000378:metabolism*; D005909:Glioblastoma / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D000069416:Intravital Microscopy; D051379:Mice; D014411:Neoplastic Stem Cells / Q000502:physiology*
chemical_list: C000601239:EFNB2 protein, human; D036388:Ephrin-B2
keywords: Eph/ephrin; GBM; cancer biology; cancer stem cells; cell biology; human; mouse; perivascular invasion