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Life sciences · Journal article
PLOS One · September 10, 2026
Encouraging direction, but not yet definitive.
This multi-cohort transcriptomic study identifies pericyte-derived cancer-associated fibroblasts as a distinct stromal population in glioblastoma with conserved signaling programs and demonstrates that high CAF signature scores correlate with poorer overall and progression-free survival, particularly in IDH-wildtype and post-chemoradiotherapy tumors. The work provides robust gene signatures and identifies CAF enrichment after standard therapy, but relies on computational deconvolution rather than experimental validation of functional causality.
Multi-cohort retrospective transcriptomic analysis with survival correlation. Glioblastoma patients from aggregated single-cell and bulk RNA sequencing cohorts; stratified by IDH mutation status and treatment history (pre- and post-chemoradiotherapy).. Intervention: CAF abundance quantified via signature scoring and computational deconvolution. Compared with: IDH-mutant vs. IDH-wildtype gliomas; pre-chemoradiotherapy vs. post-chemoradiotherapy tumors.
Continuous transcriptional spectrum identified linking endothelial cells, pericytes, and CAFs, supporting pericytes as the primary source of CAFs CAF-associated ligand–receptor interactions enriched in angiogenesis and immune modulation pathways Increased CAF abundance demonstrated in IDH-wildtype gliomas with further enrichment after chemoradiotherapy
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These findings suggest CAFs may be a biomarker for aggressive glioblastoma biology and therapy resistance, and could guide future stratification or CAF-targeting strategies. However, the observational nature and lack of functional validation mean the clinical utility and causality remain unproven and require prospective validation and mechanistic studies.
Observational multi-cohort analysis with robust transcriptomic signatures and survival correlation, but lacks experimental validation of causal mechanisms and relies on computational deconvolution rather than prospective clinical outcomes.
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These findings suggest CAFs may be a biomarker for aggressive glioblastoma biology and therapy resistance, and could guide future stratification or CAF-targeting strategies. However, the observational nature and lack of functional validation mean the clinical utility and causality remain unproven and require prospective validation and mechanistic studies.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
The role of cancer-associated fibroblasts (CAFs) in glioblastoma remains unclear, as their existence in the brain tumor microenvironment is still debated, given that the normal brain parenchyma is devoid of fibroblasts. It is unclear whether cells described as CAFs represent a distinct stromal population or a transcriptional state of perivascular cells such as pericytes. The aim of this study was to determine the identity, origin, and functional relevance of CAFs in glioblastoma. We analyzed 54 single-cell RNA sequencing datasets together with 88 bulk RNA sequencing samples. We identified a continuous transcriptional spectrum linking endothelial cells, pericytes, and CAFs, supporting pericytes as the most likely source of CAFs in glioblastoma. We further derived and validated robust CAF- and pericyte-specific gene signatures, enabling clear separation of these populations across cohorts. Reproducible CAF-associated ligand–receptor interactions were enriched in angiogenesis and immune modulation pathways. In bulk RNA-seq data, both CAF signature scoring and deconvolution consistently demonstrated increased CAF abundance in IDH-wildtype gliomas and further enrichment after chemoradiotherapy, while selective CYP1B1 expression in CAFs suggested a potential association with therapy-induced tumor adaptation. Overall, CAFs represent a distinct, pericyte-related stromal population in glioblastoma with conserved transcriptional and signaling programs. High CAF signature scores were associated with poorer overall and progression-free survival and were enriched in IDH-wildtype and post-chemoradiotherapy gliomas, suggesting a role for CAFs in therapy-associated remodeling of the tumor microenvironment in aggressive disease.
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