TY  - JOUR
A1  - Depner, Cornelia
A1  - Zum Buttel, Helge
A1  - Böğürcü, Nuray
A1  - Martinez Cuesta, Ángel
A1  - Rodriguez Aburto, Maria
A1  - Seidel, Sascha
A1  - Finkelmeier, Fabian
A1  - Foß, Franziska
A1  - Hofmann, Jan
A1  - Kaulich, Kerstin
A1  - Barbus, Sebastian
A1  - Segarra, Marta
A1  - Reifenberger, Guido
A1  - Garvalov, Boyan K.
A1  - Acker, Till
A1  - Acker-Palmer, Amparo
T1  - EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance
T2  - Nature Communications
N2  - 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.
KW  - Cancer microenvironment
KW  - Cell signalling
KW  - CNS cancer
Y1  - 2016
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/47177
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-471772
SN  - 2041-1723
N1  - 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/
VL  - 7
IS  - Art. 12329
SP  - 1
EP  - 15
PB  - Nature Publishing Group UK
CY  - [London]
ER  -