Research Papers:

Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4

Amélie Royet, Laura Broutier, Marie-May Coissieux, Céline Malleval, Nicolas Gadot, Denis Maillet, Lise Gratadou-Hupon, Agnès Bernet, Pascale Nony, Isabelle Treilleux, Jérôme Honnorat, Daniel Liebl, Laurent Pelletier, François Berger, David Meyronet, Marie Castets and Patrick Mehlen _

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Oncotarget. 2017; 8:23750-23759. https://doi.org/10.18632/oncotarget.16077

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Amélie Royet1,2, Laura Broutier1,*, Marie-May Coissieux1,*, Céline Malleval3, Nicolas Gadot4, Denis Maillet1, Lise Gratadou-Hupon1,2, Agnès Bernet1,2, Pascale Nony2, Isabelle Treilleux4, Jérôme Honnorat3, Daniel Liebl5, Laurent Pelletier6, François Berger6, David Meyronet7, Marie Castets1,#, Patrick Mehlen1,2,4,#

1Apoptosis, Cancer and Development Laboratory-Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, Lyon, France

2Netris Pharma, Lyon, France

3Lyon Neurosciences Research Center, Neuro-Oncology and Neuro-Inflammation Laboratory, INSERM UMR1028, CNRS UMR5292, Université de Lyon, Lyon, France

4Research Pathology, Department of Translational Research and Innovation, Centre Léon Bérard, Lyon, France

5University of Miami Miller School of Medicine, The Miami Project to Cure Paralysis, Miami, Fl, USA

6Grenoble Institut des Neurosciences, Nanomedicine and Brain Laboratory, INSERM U 836, BP 170, Grenoble, France

7Centre de Pathologie et de Neuropathologie Est, Hospices Civils de Lyon, Lyon, France

*These authors contributed equally to this work

#Co-senior authors

Correspondence to:

Marie Castets, email: [email protected]

Patrick Mehlen, email: [email protected]

Keywords: Ephrin-B3/EphA4, dependence receptors, glioblastoma, angiogenesis, apoptosis

Received: October 24, 2015     Accepted: February 15, 2017     Published: March 10, 2017


EphA4, an Ephrins tyrosine kinase receptor, behaves as a dependence receptor (DR) by triggering cell apoptosis in the absence of its ligand Ephrin-B3. DRs act as conditional tumor suppressors, engaging cell death based on ligand availability; this mechanism is bypassed by overexpression of DRs ligands in some aggressive cancers. The pair EphA4/Ephrin-B3 favors survival of neuronal progenitors of the brain subventricular zone, an area where glioblastoma multiform (GBM) are thought to originate. Here, we report that Ephrin-B3 is highly expressed in human biopsies and that it inhibits EphA4 pro-apoptotic activity in tumor cells. Angiogenesis is directly correlated with GBM aggressiveness and we demonstrate that Ephrin-B3 also supports the survival of endothelial cells in vitro and in vivo. Lastly, silencing of Ephrin-B3 decreases tumor vascularization and growth in a xenograft mice model. Interference with EphA4/Ephrin-B3 interaction could then be envisaged as a relevant strategy to slow GBM growth by enhancing EphA4-induced cell death.

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