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 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, ephrinB2 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.

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Author:Cornelia Depner, Helge Zum Buttel, Nuray Böğürcü, Ángel Martinez Cuesta, Maria Rodriguez Aburto, Sascha Seidel, Fabian Finkelmeier, Franziska Foss, Jan Hofmann, Kerstin Kaulich, Sebastian Barbus, Marta Segarra, Guido Reifenberger, Boyan K. Garvalov, Till AckerORCiDGND, Amparo Acker-PalmerORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/27470974
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Year of Completion:2016
Date of first Publication:2016/07/29
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/09/11
Tag:CNS cancer; Cancer microenvironment; Cell signalling
Issue:Art. 12329
Page Number:15
First Page:1
Last Page:15
Rights and permissions: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Institutes:Biowissenschaften / Biowissenschaften
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Licence (German):License LogoCreative Commons - Namensnennung 4.0