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Updated: Jun 1, 2026
Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion
Lily Keane1,2,3, Martin Škandík1,4, Mercedes Posada-Pérez1,5
1Institute of Environmental Medicine, Toxicology unit, Karolinska Institutet, Stockholm, Sweden.
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.
Insights
Microglia in diffuse midline glioma (DMG) produce fibronectin, enhancing tumor cell invasion. Targeting fibronectin may offer a new therapeutic strategy for this aggressive pediatric brain cancer.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Immunology
Background:
- Diffuse midline glioma, H3K27-altered (DMG), is a fatal pediatric brain tumor.
- Microglial infiltration is a key characteristic of DMG.
- The role of microglia in DMG progression is not fully understood.
Purpose of the Study:
- To investigate if microglia adopt a reactive state that promotes DMG progression.
- To identify specific molecular mechanisms by which microglia contribute to DMG invasiveness.
Main Methods:
- Transcriptomic profiling of microglia and tumor-associated myeloid cells from DMG patient biopsies.
- Single-cell transcriptomic analysis to identify fibronectin-expressing cells.
- Functional invasion assays using patient-derived DMG cells.
- Inhibition of fibronectin using chemical inhibitors or genetic silencing.
Main Results:
- Microglia were identified as the primary source of fibronectin in human DMG tumors.
- Microglia-derived fibronectin significantly enhanced DMG cell invasiveness.
- Inhibition or genetic silencing of fibronectin suppressed tumor cell invasion.
- Elevated fibronectin expression in DMG tumors correlated with poor prognosis across independent patient cohorts.
Conclusions:
- Microglia actively contribute to DMG invasiveness via extracellular matrix component production, specifically fibronectin.
- Fibronectin represents a potential therapeutic target for diffuse midline glioma.
- Targeting microglia-derived fibronectin could offer a novel treatment strategy for this lethal pediatric cancer.
