Journal
CANCER CELL
Volume 33, Issue 5, Pages 874-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.03.020
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Categories
Funding
- ABTA
- AACR Anna D. Barker Fellowship
- Susan Komen Fellowship
- NCI [T32CA151022, R35CA197743, P01CA080124, P50CA165962]
- Nuovo-Soldati Foundation
- UCSF Brain Tumor SPORE Tissue Core [P50CA097257]
- MGH (NFCR)
- Bryan's Dream Foundation
- Pediatric Brain Tumor Foundation
- Loglio Foundation
- HHMI
- Wellcome Trust
- NFCR
- Harvard Ludwig Cancer Center
- NINDS [NS028478, NS088114, R01CA221969, R01NS091620, NS081117, NS079697, NS088648, NS083513]
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Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanismto escape anti-angiogenic therapy, the relevance of glial phenotype in this process is unclear. We show that Olig2(+) oligodendrocyte precursor-like glioma cells invade by single-cell vessel co-option and preserve the blood-brain barrier (BBB). Conversely, Olig2-negative glioma cells form dense perivascular collections and promote angiogenesis and BBB breakdown, leading to innate immune cell activation. Experimentally, Olig2 promotes Wnt7b expression, a finding that correlates in human glioma profiling. Targeted Wnt7a/7b deletion or pharmacologic Wnt inhibition blocks Olig2(+) glioma single-cell vessel co-option and enhances responses to temozolomide. Finally, Olig2 and Wnt7 become upregulated after anti-VEGF treatment in preclinical models and patients. Thus, glial-encoded pathways regulate distinct glioma-vascular micro-environmental interactions.
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