Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches comprised of vascular endothelial cells, pericytes and extracellular matrix (ECM)-rich basement membranes. Interactions with their niche influence GSC self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the adhesion receptor alphavbeta8 integrin and its ECM-bound latent transforming growth factor beta1 (TGFbeta1) protein ligand play central roles in promoting niche co-option and GBM initiation. alphavbeta8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Inhibition of alphavbeta8 integrin adhesion and signaling using function-blocking antibodies inhibit sphere formation in vitro. Fractionation of beta8high cells from freshly resected human GBM samples also reveals a requirement for this integrin in sphere formation in vitro and tumor growth and invasion in vivo. In contrast, fractionated beta8low GBM cells fail to form spheroids in vitro and do not generate tumors after intracranial implantation. Whole transcriptome sequencing of primary GBM cells reveals that alphavbeta8 integrin promotes tumor initiation in the brain, in large part, by driving TGFbeta1-induced DNA replication and mitotic checkpoint progression. We show that beta8high cells activate latent TGFbeta1 in the microenvironment, resulting in enhanced TGFbeta receptor signaling in beta8low GBM cells and tumor endothelial cells via Smad transcription factors. Collectively, these data identify the alphavbeta8 integrin-TGFbeta1 signaling axis as crucial for exploitation of the perivascular niche and identify potential therapeutic targets for inhibiting tumor growth and progression in patients with GBM.
