Nicolas Goffart1, Arnaud Lombard1, François Lallemand1, Jérôme Kroonen1, Jessica Nassen1, Emmanuel Di Valentin1, Sharon Berendsen2, Matthias Dedobbeleer1, Estelle Willems1, Pierre Robe1, Vincent Bours1, Didier Martin1, Philippe Martinive1, Pierre Maquet1, Bernard Rogister1. 1. Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium (N.G., A.L., J.N., M.D., E.W., B.R.); Department of Neurosurgery, CHU and University of Liège, Liège, Belgium (A.L., D.M.); Department of Radiotherapy and Oncology, CHU and University of Liège, Liège, Belgium (F.L., P.M.); Laboratory of Tumor and Development Biology, GIGA-Cancer Research Center, University of Liège, Liège, Belgium (F.L.); Cyclotron Research Centre, University of Liège, Liège, Belgium (F.L.); Human Genetics, CHU and University of Liège, Liège, Belgium (N.G., J.K., V.B.); Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences and the T&P Bohnenn Laboratory for Neuro-Oncology University Medical Center, Utrecht, The Netherlands (N.G., J.K., S.B., P.R.); GIGA-Viral Vector Plateform, University of Liège, Liège, Belgium (E.D.V.); Department of Neurology, CHU and University of Liège, Liège, Belgium (P.M., B.R.). 2. Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium (N.G., A.L., J.N., M.D., E.W., B.R.); Department of Neurosurgery, CHU and University of Liège, Liège, Belgium (A.L., D.M.); Department of Radiotherapy and Oncology, CHU and University of Liège, Liège, Belgium (F.L., P.M.); Laboratory of Tumor and Development Biology, GIGA-Cancer Research Center, University of Liège, Liège, Belgium (F.L.); Cyclotron Research Centre, University of Liège, Liège, Belgium (F.L.); Human Genetics, CHU and University of Liège, Liège, Belgium (N.G., J.K., V.B.); Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences and the T&P Bohnenn Laboratory for Neuro-Oncology University Medical Center, Utrecht, The Netherlands (N.G., J.K., S.B., P.R.); GIGA-Viral Vector Plateform, University of Liège, Liège, Belgium (E.D.V.); Department of Neurology, CHU and University of Liège, Liège, Belgium (P.M., B.R.) bernard.rogister@ulg.ac.be.
Abstract
BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.
BACKGROUND:Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.
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