Journal
ONCOGENE
Volume 36, Issue 47, Pages 6568-6580Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2017.248
Keywords
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Funding
- NIH/NINDS [R01NS0 7635, R01NS078402]
- Cancer Prevention and Research Institute of Texas [RP140411]
- NIH/NCI SPORE in Brain Cancer [P50CA127001]
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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.
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