RT Journal Article
T1 EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance
A1 Depner, C.
A1 Buttel, H. zum
A1 Böğürcü, N.
A1 Cuesta, A. M.
A1 Aburto, M. R.
A1 Seidel, S.
A1 Finkelmeier, F.
A1 Foss, F.
A1 Hofmann, J.
A1 Kaulich, K.
A1 Barbus, S.
A1 Segarra, M.
A1 Reifenberger, G.
A1 Garvalov, B. K.
A1 Acker, T.
A1 Acker-Palmer, Amparo
AB Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with 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 gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, <jats:italic>ephrinB2</jats:italic> gene silencing is 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 gliomas and 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.
PB Nature Research
YR 2016
FD 2016
LK https://hdl.handle.net/20.500.14352/93833
UL https://hdl.handle.net/20.500.14352/93833
LA eng
NO Depner C, Zum Buttel H, Böğürcü N, et al. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nat Commun. 2016;7:12329. Published 2016 Jul 29. doi:10.1038/ncomms12329
NO Deutsche Forschungsgemeinschaft
NO Behring-Röntgen Foundation
NO Johannes Gutenberg Universität Mainz
NO Deutsche Krebshilfe
NO Bundesministerium für Forschung, Technologie und Raumfahrt (Deutschland)
NO National Genome Network
NO Brain Tumor Network
NO Clusters of Excellence ‘Macromolecular Complexes'
NO ustus-Liebig-Universität Gießen
DS Docta Complutense
RD 25 dic 2025