A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment

Publication date: Available online 19 April 2018
Source:Cancer Cell
Author(s): Amelie Griveau, Giorgio Seano, Samuel J. Shelton, Robert Kupp, Arman Jahangiri, Kirsten Obernier, Shanmugarajan Krishnan, Olle R. Lindberg, Tracy J. Yuen, An-Chi Tien, Jennifer K. Sabo, Nancy Wang, Ivy Chen, Jonas Kloepper, Louis Larrouquere, Mitrajit Ghosh, Itay Tirosh, Emmanuelle Huillard, Arturo Alvarez-Buylla, Michael C. Oldham, Anders I. Persson, William A. Weiss, Tracy T. Batchelor, Anat Stemmer-Rachamimov, Mario L. Suvà, Joanna J. Phillips, Manish K. Aghi, Shwetal Mehta, Rakesh K. Jain, David H. Rowitch
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.

Teaser

Griveau et al. show that Olig2⁺ glioma cells invade by single-cell vessel co-option, whereas Olig2⁻ 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.


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