EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance.

Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomaswith various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomasas a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade gliomamodel increases invasion. Importantly, ephrinB2 gene silencingis complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor(HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomasand is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.