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| Item Type: | Article |
|---|---|
| Title: | Host TLR4 activation by tenascin-C is associated with MMP14-dependent glioma invasion |
| Creators: |
Haneke, Hannah  ORCID: https://orcid.org/0009-0004-0033-9984, Efe, Ibrahim E. ORCID: https://orcid.org/0000-0002-4232-3305, Dzaye, Omar, Kettenmann, Helmut ORCID: https://orcid.org/0000-0001-8208-0291 and Yalcin, Fatih ORCID: https://orcid.org/0000-0001-6325-9018
|
| Abstract: | Glioblastoma is the most aggressive primary brain tumor in adults and is characterized by diffuse invasion and profound remodeling of the tumor microenvironment. Tumor-associated microglia and macrophages represent the largest non-malignant population in glioblastoma and promote invasive growth through context-dependent inflammatory and matrix-remodeling programs, yet the endogenous microenvironmental cues that drive their pro-invasive activation remain incompletely defined. Tenascin-C (TNC) is an extracellular matrix glycoprotein abundantly expressed in glioblastoma and a reported endogenous ligand of Toll-like receptor 4 (TLR4). Here, we investigated whether tumor-derived TNC engages TLR4 signaling in host myeloid cells, consistent with a role to promote glioma invasion through induction of matrix metalloproteinases. To this end, we combined analyses of freshly resected human glioblastoma specimens, public bulk sequencing and CISH datasets, ex vivo GL261-organotypic brain slice cultures from wild-type and TLR4-deficient mice, and primary murine microglia cultures. TLR4 expression in human glioblastoma was enriched in CD11b(+) tumor-associated myeloid cells and was linked to immunoregulatory rather than pro-inflammatory macrophage signatures. TNC was strongly upregulated in tumor tissue, derived predominantly from non-myeloid CD45(-) cells, and was spatially enriched in invasive and perivascular regions, where it was juxtaposed to reactive Iba1(+) microglia displaying an amoeboid morphology. Across independent glioma cohorts, TNC expression correlated with the membrane-anchored matrix-remodeling protease MMP14, particularly within anatomically defined invasive tumor compartments, and combined high TNC and MMP14 expression was associated with shorter overall survival. Functionally, host TLR4 deficiency reduced glioma growth and infiltrative expansion in organotypic brain slices, and in primary microglia, TNC induced a robust upregulation of MMP14 that was markedly attenuated in TLR4-deficient cells, whereas MMP9 regulation was modest and only partially TLR4-dependent. Cell-type-resolved single-nucleus and ligand-receptor analysis (CellChat/LIANA+) in two independent datasets (BrainTIME, GBM-CARE) further supported directional TNC-TLR4 communication from non-myeloid/malignant to myeloid populations. Together, these findings support a model in which tumor-derived TNC contributes to TLR4 activation in host myeloid cells and is associated with a pro-invasive microenvironmental program involving MMP14 induction in GBM. The identified TNC–TLR4–MMP14 signaling axis links extracellular matrix remodeling with innate immune activation, which highlights a potential tumor immune mechanism contributing to glioma invasion. |
| Keywords: | Glioblastoma, Glioma Invasion, Innate Immune Activation, MMP14, Tenascin-C (TNC), Toll-Like Receptor 4, Tumor Immune Microenvironment, Tumor-Associated Microglia/ Macrophages (TAM) |
| Source: | Frontiers in Oncology |
| ISSN: | 2234-943X |
| Publisher: | Frontiers Media SA |
| Volume: | 16 |
| Page Range: | 1915071 |
| Date: | 8 September 2026 |
| Official Publication: | https://doi.org/10.3389/fonc.2026.1915071 |
| Related to: |
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