title: EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance.
abstract: 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.
authors.affiliation: Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Depner
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Zum Buttel
authors.affiliation: Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Böğürcü
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
authors.forename: A M
authors.initials: AM
authors.lastname: Cuesta
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.|Focus Program Translational Neurosciences (FTN), University of Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: M R
authors.initials: MR
authors.lastname: Aburto
authors.affiliation: Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Seidel
authors.affiliation: Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Finkelmeier
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.|Focus Program Translational Neurosciences (FTN), University of Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Foss
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hofmann
authors.affiliation: Department of Neuropathology, Heinrich Heine University of Düsseldorf, Düsseldorf and German Cancer Consortium (DKTK), Moorenstr. 5, 40225 partner site Essen/Düsseldorf, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kaulich
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Barbus
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Segarra
authors.affiliation: Department of Neuropathology, Heinrich Heine University of Düsseldorf, Düsseldorf and German Cancer Consortium (DKTK), Moorenstr. 5, 40225 partner site Essen/Düsseldorf, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Reifenberger
authors.affiliation: Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
authors.forename: B K
authors.initials: BK
authors.lastname: Garvalov
authors.affiliation: Institute of Neuropathology, University of Giessen, Arndtstr. 16, D-35392 Giessen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Acker
authors.affiliation: Institute of Cell Biology and Neuroscience and Buchmann Institute for Molecular Life Sciences (BMLS), University of Frankfurt, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.|Focus Program Translational Neurosciences (FTN), University of Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany.|Max Planck Institute for Brain Research, Max-von-Laue Str. 4, 60438 Frankfurt, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Acker-Palmer
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000068258:Bevacizumab / Q000494:pharmacology / Q000627:therapeutic use; D015687:Cell Hypoxia / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D036388:Ephrin-B2 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000098:blood supply / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000074165:Zinc Finger E-box Binding Homeobox 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D020533:Angiogenesis Inhibitors; D036388:Ephrin-B2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000068258:Bevacizumab