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Mesenchymal transtion in glioblastoma is mediated by ZEB1 and contributes to tumor heterogeneity

Frank A. Kruyt, Department of Medical Oncology, University of Groningen, University Medical Center Groningen P.O.box 30001, 9700RB Groningen; Justin Joseph, Department of Medical Oncology, University of Groningen, University Medical Center Groningen P.O.box 30001, 9700RB Groningen; Siobhan Conroy, Department of Pathology, University of Groningen, University Medical Center Groningen P.O.box 30001, 9700RB Groningen; Ellie Eggens-Meijer, Department of Neurosciences, University of Groningen, P.O.box 30001, 9700RB Groningen; Michiel Wagemakers, Department of Neurosurgery, University Medical Center Groningen P.O.box 30001, 9700RB Groningen; Wilfred den Dunnen, Department of Pathology, University Medical Center Groningen P.O.box 30001, 9700RB Groningen


In glioblastoma (GBM) different molecular subtypes have been identified of which the proneural (PN) and mesenchymal (MES) subtypes are most pronounced. The MES subtype has been associated with enhanced aggressiveness and worse prognosis.
We have examined whether external stimuli can regulate a mesenchymal status in GBM in analogy with the activation of epithelial-mesenchymal transition (EMT) in carcinomas, known to facilitate the invasive behavior of tumor cells. Interestingly, we found that two different stimuli that are well known for playing a role in the aggressiveness of GBM, TGF-ß and hypoxia, are able to induce a mesenchymal transition in non-MES adherent - and newly established GBM neurospheres. Mesenchymal transition in GBM was accompanied by enhanced migration and invasion as demonstrated in in vitro and in vivo experiments. Knock down of the EMT transcription factor ZEB1 prevented both hypoxia- and TGF-ß-induced mesenchymal transition. Mesenchymal transition occurred in a cell specific way, some cells being responsive and others non-responsive to TGF-ß. In addition, some GBM cells were sensitive to TGF-ß but resistant to hypoxia–induced mesenchymal transition. In GBM patient material zones with overlapping expression of markers for TGF-ß signaling (pSMAD2) or hypoxia (GLUT1), with ZEB1 and the mesenchymal marker YKL40 were detected.
Overall, we demonstrated that external stimuli can induce a mesenchymal transition in GBM cells leading to enhanced invasive capacity in which ZEB1 plays an essential role. This process will contribute to heterogeneity in GBM and makes a sharp distinction between PN and MES subtypes in GBM less likely. Targeting mechanisms of mesenchymal transition may lead to therapeutic benefit in GBM.

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