2026-06-14T03:40:33Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/78882024-11-29T21:58:05Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Krusche, Benjamin author Ottone, Cristina author Clements, Melanie P author Johnstone, Ewan R author Goetsch, Katrin author Lieven, Huang author Mota, Silvia G author Singh, Poonam author Khadayate, Sanjay author Ashraf, Azhaar author Davies, Timothy author Pollard, Steven M author De Paola, Vincenzo author Roncaroli, Federico author Martinez Torrecuadrada, Jorge Luis author Bertone, Paul author Parrinello, Simona author 2016-06-28 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. Elife. 2016;5. pii: e14845. 10.7554/eLife.14845 2050-084X 2050-084X eLife 27350048 http://hdl.handle.net/20.500.12105/7888 Eph/ephrin GBM Cancer biology Cancer stem cells Cell biology Human Nouse Perivascular invasion EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells