A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches

Interactions among tumor, immune, and vascular niches play major roles in glioblastoma (GBM) malignancy and treatment responses. The composition and heterogeneity of extracellular core matrix proteins (CMPs) that mediate such interactions are not well understood. Here, we present an analysis of the clinical relevance of CMP expression in GBM at bulk, single-cell, and spatial anatomical resolution. We show that CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, pro-tumor immune infiltration, and immune checkpoint expression. Matrisome expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells. Finally, we identify a 17-gene CMP signature, termed Matrisome 17 (M17), which is a stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, may predict responses to PD1 blockade. Patient stratification based on matrisome profiles can contribute to the selection and optimization of treatment strategies.