Host TLR4 activation by tenascin-C is associated with MMP14-dependent glioma invasion.

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