A Glial Signature and Wnt7 Signaling Regulate Glioma-Vascular Interactions and Tumor Microenvironment.
Authors | |
Keywords | |
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. |
Year of Publication | 2018
|
Journal | Cancer Cell
|
Volume | 33
|
Issue | 5
|
Pages | 874-889.e7
|
Date Published | 2018 05 14
|
ISSN | 1878-3686
|
DOI | 10.1016/j.ccell.2018.03.020
|
PubMed ID | 29681511
|
PubMed Central ID | PMC6211172
|
Links | |
Grant list | R21 NS088114 / NS / NINDS NIH HHS / United States
R01 NS091620 / NS / NINDS NIH HHS / United States
T32 CA151022 / CA / NCI NIH HHS / United States
R01 CA221969 / CA / NCI NIH HHS / United States
R35 CA197743 / CA / NCI NIH HHS / United States
P50 CA097257 / CA / NCI NIH HHS / United States
P01 CA080124 / CA / NCI NIH HHS / United States
R01 CA208205 / CA / NCI NIH HHS / United States
WT_ / Wellcome Trust / United Kingdom
R01 NS079697 / NS / NINDS NIH HHS / United States
MC_PC_12009 / MRC_ / Medical Research Council / United Kingdom
P01 NS083513 / NS / NINDS NIH HHS / United States
R01 NS028478 / NS / NINDS NIH HHS / United States
R01 NS088648 / NS / NINDS NIH HHS / United States
R01 NS081117 / NS / NINDS NIH HHS / United States
P50 CA211015 / CA / NCI NIH HHS / United States
R37 NS028478 / NS / NINDS NIH HHS / United States
P50 CA165962 / CA / NCI NIH HHS / United States
|