Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/7888
EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells
Krusche, Benjamin | Ottone, Cristina | Clements, Melanie P | Johnstone, Ewan R | Goetsch, Katrin | Lieven, Huang | Mota, Silvia G | Singh, Poonam | Khadayate, Sanjay | Ashraf, Azhaar | Davies, Timothy | Pollard, Steven M | De Paola, Vincenzo | Roncaroli, Federico | Martinez Torrecuadrada, Jorge Luis CNIO | Bertone, Paul | Parrinello, Simona
Elife. 2016;5. pii: e14845.
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.
Eph/ephrin | GBM | cancer biology | cancer stem cells | cell biology | human | mouse | perivascular invasion
Animals | Ephrin-B2 | Glioblastoma | Heterografts | Humans | Intravital Microscopy | Mice | Neoplastic Stem Cells | Cell Movement | Cell Proliferation
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