1. A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment
- Author
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Griveau, Amelie, Seano, Giorgio, Shelton, Samuel J, Kupp, Robert, Jahangiri, Arman, Obernier, Kirsten, Krishnan, Shanmugarajan, Lindberg, Olle R, Yuen, Tracy J, Tien, An-Chi, Sabo, Jennifer K, Wang, Nancy, Chen, Ivy, Kloepper, Jonas, Larrouquere, Louis, Ghosh, Mitrajit, Tirosh, Itay, Huillard, Emmanuelle, Alvarez-Buylla, Arturo, Oldham, Michael C, Persson, Anders I, Weiss, William A, Batchelor, Tracy T, Stemmer-Rachamimov, Anat, Suvà, Mario L, Phillips, Joanna J, Aghi, Manish K, Mehta, Shwetal, Jain, Rakesh K, and Rowitch, David H
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Neurosciences ,Rare Diseases ,Cancer ,Brain Cancer ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Animals ,Bevacizumab ,Blood-Brain Barrier ,Brain Neoplasms ,Cell Line ,Tumor ,Gene Expression Regulation ,Neoplastic ,Glioma ,Humans ,Mice ,Neoplasm Transplantation ,Oligodendrocyte Transcription Factor 2 ,Oligodendroglia ,Temozolomide ,Tumor Cells ,Cultured ,Tumor Microenvironment ,Wnt Proteins ,Wnt Signaling Pathway ,Olig2 ,Wnt ,angiogenesis ,astrocyte ,blood-brain barrier ,glioma ,invasiveness ,oligodendrocyte precursor ,p53 ,vessel co-option ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Gliomas comprise heterogeneous malignant glial and stromal cells. While blood vessel co-option is a potential mechanism to 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 microenvironmental interactions.
- Published
- 2018