The white matter is a pro-differentiative niche for glioblastoma

Lucy J Brooks, Melanie P Clements, Jemima J Burden, Daniela Kocher, Luca Richards, Sara Castro Devesa, Leila Zakka, Megan Woodberry, Michael Ellis, Zane Jaunmuktane, Sebastian Brandner, Gillian Morrison, Steven M Pollard, Peter B Dirks, Samuel Marguerat, Simona Parrinello

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Glioblastomas are hierarchically organised tumours driven by glioma stem cells that retain partial differentiation potential. Glioma stem cells are maintained in specialised microenvironments, but whether, or how, they undergo lineage progression outside of these niches remains unclear. Here we identify the white matter as a differentiative niche for glioblastomas with oligodendrocyte lineage competency. Tumour cells in contact with white matter acquire pre-oligodendrocyte fate, resulting in decreased proliferation and invasion. Differentiation is a response to white matter injury, which is caused by tumour infiltration itself in a tumoursuppressive feedback loop. Mechanistically, tumour cell differentiation is driven by selective white matter upregulation of SOX10, a master regulator of normal oligodendrogenesis. SOX10 overexpression or treatment with myelination-promoting agents that upregulate endogenous SOX10, mimic this response, leading to niche-independent pre-oligodendrocyte differentiation and tumour suppression in vivo. Thus, glioblastoma recapitulates an injury response and exploiting this latent programme may offer treatment opportunities for a subset of patients.

Original languageEnglish
Pages (from-to)2184
JournalNature Communications
Volume12
Issue number1
DOIs
Publication statusPublished - 12 Apr 2021

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Brain Neoplasms/pathology
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma/pathology
  • Mice, Inbred NOD
  • Mice, SCID
  • Myelin Sheath/metabolism
  • Oligodendroglia/pathology
  • SOXE Transcription Factors/metabolism
  • Transcriptome/genetics
  • Up-Regulation/genetics
  • White Matter/pathology

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