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Extracellular Matrix ECM Remodeling Marks an Injury Like Transcriptional State Associated with Poor Survival in Glioblastoma

Lehrer, S.; Rheinstein, P.

2025-11-25 oncology
10.1101/2025.11.22.25340791 medRxiv
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BackgroundGlioblastoma (GBM) progression is strongly influenced by its microenvironment, yet the contribution of white-matter injury-associated extracellular matrix (ECM) remodeling to human disease remains unclear. Experimental models show that glioma cells induce axonal injury and glial-scar-like ECM responses that accelerate tumor growth. MethodsWe curated an ECM Organization Signature reflecting injury-associated matrix remodeling and applied it to bulk RNA-sequencing data from TCGA-GBM. ECM scores were analyzed alongside wound-healing, microglia/TAM activation, and neuronal integrity signatures. Kaplan-Meier curves and age-adjusted Cox models assessed prognostic significance. ResultsECM organization, wound-healing, and microglia/TAM activation formed a coherent injury-response axis inversely correlated with neuronal programs. ECM-high tumors showed significantly different overall survival compared with ECM-low tumors (log-rank p = 0.023). In an age-adjusted Cox model, ECM remodeling independently predicted mortality (HR = 1.23, p = 0.0156). ConclusionWhite-matter injury-associated ECM remodeling is a prominent, clinically meaningful transcriptional state in human GBM and identifies a prognostic microenvironmental subtype.

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