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  3. Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance

Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance

  • Neuron. 2026 Jan 21;114(2):237-249.e10. doi: 10.1016/j.neuron.2025.12.012.
Nicholas Mikolajewicz 1,  Kui Zhai 2,  Anish Puri 3,  Petar Miletic 2,  Nazanin Tatari 3,  Jiarun Wei 4,  Neil Savage 2,  Zhi Huang 5,  Qian Huang 5,  Seon Yong Lee 1,  Mahta Jan-Ahmadnejad 6,  Roseanne Nguyen 6,  David Chen 1,  Tiegan Korman 3,  Daniel Mobilio 3,  Maxwell Topley 3,  Jack Qinyu Lu 3,  Matthew R Voisin 7,  Zsolt Zador 8,  Shawn C Chafe 2,  Chitra Venugopal 2,  Kevin R Brown 1,  Gelareh Zadeh 7,  Hong Han 3,  Julien Muffat 6,  Shideng Bao 9,  Sheila K Singh 10,  Jason Moffat 11
Affiliations

Affiliations

  • 1 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
  • 2 Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
  • 3 Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada.
  • 4 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
  • 5 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 6 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Program for Developmental, Stem Cell and Cancer Biology, Program for Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, ON, Canada.
  • 7 MacFeeters Hamilton Neuro-Oncology Program, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada.
  • 8 Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
  • 9 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; Center for Cancer Stem Cell Research, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  • 10 Centre for Discovery in Cancer Research (CDCR), McMaster University, Hamilton, ON, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, Canada; Department of Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada. Electronic address: [email protected].
  • 11 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Institute for Biomedical Engineering, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected].
PMID: 41570802 DOI: 10.1016/j.neuron.2025.12.012
Abstract

Glioblastoma (GBM) evolves within a microenvironment abundant in oligodendrocyte-lineage (OL) cells. In this study, we utilized single-cell and spatial transcriptomics from primary and recurrent GBM tumors, immunohistochemistry, cytokine profiling, and migration assays to show that GBM cells recruit OLs to the tumor border via fractalkine (i.e., CX3CL1/CX3CR1) signaling. A pan-disease human OL meta-atlas and syngeneic mouse models reveal an interferon (IFN)-induced reactive OL state, akin to those seen in demyelinating inflammatory and traumatic injury, which is enriched in central nervous system malignancies. These reactive OLs secrete pro-tumorigenic cytokines, notably C-C motif chemokine ligand 5 (CCL5), that promote GBM tumor cell growth through C-C Chemokine Receptor type 5 (CCR5) signaling. CCR5 is preferentially expressed in glioma stem-like cells (GSCs) and upregulated at recurrence. Targeting CCR5 with genetic knockdown or the approved drug maraviroc impairs GSC stemness and prolongs survival in GBM models. Our work highlights the functional interplay between OLs and GBM cells and positions the CCL5/CCR5 axis as a druggable target in GBM.

Keywords

CCL5; CCR5; CX3CL1; CX3CR1; glioblastoma; glioma stem cells; maraviroc; oligodendrocyte progenitor cells; oligodendrocytes; single-cell transcriptomics.

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