title: CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse.
authors.affiliation: 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.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goffart
authors.affiliation: 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.).
authors.forename: Arnaud
authors.initials: A
authors.lastname: Lombard
authors.affiliation: 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.).
authors.forename: François
authors.initials: F
authors.lastname: Lallemand
authors.affiliation: 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.).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kroonen
authors.affiliation: 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.).
authors.forename: Jessica
authors.initials: J
authors.lastname: Nassen
authors.affiliation: 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.).
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Di Valentin
authors.affiliation: 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.
authors.forename: Sharon
authors.initials: S
authors.lastname: Berendsen
authors.affiliation: 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.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Dedobbeleer
authors.affiliation: 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.).
authors.forename: Estelle
authors.initials: E
authors.lastname: Willems
authors.affiliation: 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.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Robe
authors.affiliation: 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.).
authors.forename: Vincent
authors.initials: V
authors.lastname: Bours
authors.affiliation: 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.).
authors.forename: Didier
authors.initials: D
authors.lastname: Martin
authors.affiliation: 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.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Martinive
authors.affiliation: 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.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Maquet
authors.affiliation: 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.).
authors.forename: Bernard
authors.initials: B
authors.lastname: Rogister
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D054377:Chemokine CXCL12 / Q000378:metabolism*; D016371:Cranial Irradiation / Q000009:adverse effects*; D005720:Gamma Rays / Q000009:adverse effects; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D020547:Lateral Ventricles / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000528:radiation effects; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000528:radiation effects; D014407:Tumor Cells, Cultured
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12
keywords: CXCL12; glioblastoma; mesenchymal activation; radioresistance; subventricular zone