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.
Highlights
Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour and one of the most lethal types of cancer (Chen et al, 2012b)
To investigate mechanisms of glioblastoma stem-like cells (GSC)/vascular interactions in the context of syngeneic, immuno-competent brains, we sequentially introduced mutations commonly found in human GBM (RTK activation,p53 and RB inactivation) in primary murine SVZ neural stem cells (NSC) to generate fully transformed, GSC-like cells and genetically-matched immortalised NSC (Network, 2008)
We used a ‘classical’ transformation paradigm previously shown to drive gliomagenesis in vivo, whereby NSC were immortalised with SV40 large-T antigen and transformed with RasV12 to inactivate Trp53 and Rb, and mimic the increased Ras signalling that results from Nf1 loss, respectively (Blouw et al, 2003; Hahn et al, 1999; Sonoda et al, 2001; Huszthy et al, 2012)
Summary
Glioblastoma (GBM) is the most common and aggressive type of primary brain tumour and one of the most lethal types of cancer (Chen et al, 2012b). Current therapies consist of maximally safe surgical resection followed by radio and chemotherapy. Cancer biology Cell biology eLife digest Glioblastoma is the most common and deadly type of brain cancer. One of the main reasons that therapy fails is the strong tendency of the tumor cells in this form of cancer to spread into the normal brain tissue. This makes it impossible for surgeons to completely remove the tumor, which means that the disease will almost always recur
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