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Mesenchymal Activation Mediated by CXCL12 in the Sub-ventricular Zone Promotes Glioblastoma Resistance to Radiotherapy.

Nicolas Goffart (1), Arnaud Lombard (1,2), Jérôme Kroonen (3, 4), Jessica Nassen (1), Matthias Dedobbeleer (1), Philippe Martinive (5), Bernard Rogister (1, 6, 7)

1 Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium
2 Department of Neurosurgery, CHU and University of Liège, Liège, Belgium
3 Human Genetics, CHU and University of Liège, Liège, Belgium
4 The T&P Bohnenn Laboratory for Neuro-Oncology, Department of Neurosurgery, UMC Utrecht, Utrecht, The Netherlands
5 Department of Radiotherapy and Oncology, CHU and University of Liège, Liège, Belgium
6 Department of Neurology, CHU and University of Liège, Liège, Belgium
7 GIGA-Development, Stem Cells and Regenerative Medicine, University of Liège, Liège, Belgium


Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months despite multimodal therapy. This catastrophic survival rate is the consequence of systematic relapses which may arise from remaining glioblastoma stem cells (GSC) left behind after surgery. We and others have previously demonstrated that GSC are able to escape the tumor mass and specifically colonize the adult sub-ventricular zone (SVZ) after transplantation. This specific location, away from the initial tumor site, may therefore represent a high-quality model of clinical obstacle to therapy and relapses since GSC retain the ability to form secondary tumors. Relying on recent findings demonstrating the existence of GSC in the human SVZ and their potential implication in therapeutic resistance, we wondered whether the SVZ could endorse the role of an efficient GSC reservoir, potentially involved in malignant brain tumor relapses.
In this context, we demonstrated SVZ-nested GSC to be specifically resistant to radiation in vivo. Interestingly, these cells displayed an enhanced mesenchymal phenotype compared to GBM cells present in the tumor mass. These mesenchymal traits were further shown to be up-regulated upon CXCL12 stimulation in vitro. In this line, we and others previously reported the SVZ to be source of CXCL12 in the adult brain. We finally demonstrated SVZ-released CXCL12 to mediate GBM resistance to irradiation in vitro. Taken together, these data suggest the critical role undertaken by SVZ-released CXCL12 in mediating GBM resistance to radiotherapy through the mesenchymal activation of GBM cells and underpin the adult SVZ stem cell niche as a potential environment involved in GBM radioresistance.

Key words: Glioblastoma, Radioresistance, Sub-ventricular Zone, Mesenchymal Activation, CXCL12.

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