Glioblastoma stem cells exploit the alpha v beta 8 integrin-TGF beta 1 signaling axis to drive tumor initiation and progression

摘要

Glioblastoma (GBM) is a primary brain cancer that contains populations of stem-like cancer cells (GSCs) that home to specialized perivascular niches. GSC interactions with their niche influence self-renewal, differentiation and drug resistance, although the pathways underlying these events remain largely unknown. Here, we report that the integrin alpha v beta 8 and its latent transforming growth factor beta 1 (TGF beta 1) protein ligand have central roles in promoting niche co-option and GBM initiation. alpha v beta 8 integrin is highly expressed in GSCs and is essential for self-renewal and lineage commitment in vitro. Fractionation of beta 8(high) cells from freshly resected human GBM samples also reveals a requirement for this integrin in tumorigenesis in vivo. Whole-transcriptome sequencing reveals that alpha v beta 8 integrin regulates tumor development, in part, by driving TGF beta 1-induced DNA replication and mitotic checkpoint progression. Collectively, these data identify the av beta 8 integrin-TGF beta 1 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.