Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion.

Overview

1. Institute of Environmental Medicine, Toxicology unit, Karolinska Institutet, Stockholm, Sweden
2. Present Address: APC Microbiome Ireland, University College Cork, Cork, Ireland
3. Present Address: Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland
4. Present Address: Ribocure Pharmaceuticals AB, Gothenburg, Sweden
5. Center for Neuromusculoskeletal Restorative Medicine, Hong Kong Science Park, Shatin, Hong Kong, China
6. Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
7. Morgan Adams Foundation Pediatric Brain Tumor Research Foundation, Department of Pediatrics, University of Colorado Anschutz Medical Campus Aurora, Aurora, CO USA

Abstract

Diffuse midline glioma, H3K27-altered (DMG), is an aggressive and uniformly fatal paediatric brain tumour arising in midline structures and characterised by substantial microglial infiltration. We investigated whether microglia adopt a reactive state in response to DMG cells that functionally contributes to tumour progression. Transcriptomic profiling of microglia exposed to DMG, H3K27M cells, together with analysis of tumour associated myeloid cells isolated from DMG patient biopsies, revealed a pronounced upregulation of extracellular matrix (ECM) components, including fibronectin. Single cell transcriptomic analysis further identified microglia as the primary fibronectin expressing cell population within human DMG, H3K27M tumours. Functional invasion assays using a panel of patient-derived DMG, H3K27M cells, revealed that microglia-derived fibronectin significantly enhances tumour cell invasiveness, while its chemical inhibition with RGDS peptide or Avapritinib or its genetic silencing using small-interfering RNAs effectively suppresses invasion. Across independent patient cohorts (Kids First, PNOC, and CBTTC), and in archival tissues, DMG tumours were found to exhibit elevated expression of ECM components, and high fibronectin expression that correlated with poor prognosis. These findings suggest that microglia actively contribute to DMG invasiveness through ECM component production, identifying fibronectin as a potential therapeutic target in this lethal paediatric cancer.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• geo:GSE126025, at NCBI GEO; found in the text, “Patient sample single-cell RNA-Seq analysis”

Data availability

The transcriptome dataset comparing BV-2 microglia exposed to SF8628 DMG cells or SF188 pHGG cells is available at the Gene Expression Omnibus with accession number: GSE309866. The bulk RNA-seq and scRNA-seq from human DMG biopsies are already published [24, 41]. All other data are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Funding: added Vetenskapsrådet

Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 2 keywords, 10 MeSH terms, 69 references, 5 RRIDs.

Cite

This paper

Keane, L., Škandík, M., Posada-Pérez, M., Bose, R., Desito, J., van der Linde, E., Engskog-Vlachos, P., Ceccatelli, S., Green, A. L., & Joseph, B. (2026). Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion. Cell death & disease, 17(1), 517. https://doi.org/10.1038/s41419-026-08891-y

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