ANGI-04Olig2 REGULATES Wnt7b EXPRESSION AND VASCULATURE CHARACTERISTICS IN GLIOMA

Treatment of malignant gliomas has been a challenge due to their transient response to surgical resection and inhibitors of VEGF signaling. Recurrent tumors become resistant to anti-angiogenesis inhibitors and were proposed to convert to a mode of vessel “co-option” whereby they invade into brain parenchyma along the pre-existing vasculature. The genetic and signaling mechanisms that govern vascular co-option just recently started to be investigated and remain poorly understood. We have recently shown that immature oligodendrocyte precursors (OPCs) regulate angiogenesis in developing white matter through canonical Wnt7 signaling. In this study, we show that mRNA levels of OLIG2 and other OPC signature genes strongly correlate with WNT7B in human gliomas, especially oligodendroglioma. OLIG2+ oligodendroglial cells express high levels of WNT7A/B in close vicinity to vascular endothelial cells that express the Wnt target, LEF1. Furthermore, we demonstrate that Olig2 function regulates OPC-like features, Wnt7a/7b expression/activity and enhanced migration along a pre-existing vasculature in a p53-null murine glioma model. Conversely, Olig2-null tumors showed increased vascular density, VEGF expression and limited migration. We report that p53 acts as a direct repressor of the Wnt7b locus and that Olig2 promotes Wnt7b expression in a p53-mutant context. Intracranial administration of the Wnt inhibitor XAV939 with mouse oligodendroglioma cells significantly affected vessel density and migration of tumor cells. Finally, we observed selective upregulation of Wnt7b expression in a model of VEGF-resistant glioma. These findings indicate that OPC-like cells in glioma promote Wnt7b signaling providing an alternative pathway to VEGF signaling.