A Glial Signature And Wnt7 Signaling Regulate Glioma-Vascular Interactions And Tumor Microenvironment
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. Griveau et al. show that Olig2+ glioma cells invade by single-cell vessel co-option, whereas Olig2âˆ’ glioma cells promote angiogenesis and that anti-VEGF treatment selects for the Olig2+/Wnt7+ phenotype. Wnt7 is necessary for vessel co-option, and Wnt inhibition enhances the response to temozolomide treatment.
Digital Object Identifier (DOI)
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; SuvÃ, Mario L.; Phillips, Joanna J.; Aghi, Manish K.; Mehta, Shwetal; Jain, Rakesh K.; and Rowitch, David H., "A Glial Signature And Wnt7 Signaling Regulate Glioma-Vascular Interactions And Tumor Microenvironment" (2018). Translational Neuroscience. 289.