ArticleFrontiers in immunology2025
Single-cell/spatial integration reveals an MES2-like glioblastoma program orchestrated by immune communication and regulatory networks.
Article in Frontiers in immunology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Oxiracetam Improves Cognitive Disorder in AD by Modulating AMPAR Subunits GluA1/GluA2 Kinetics.Cell biochemistry and biophysics · 2026Article
- Modulation of Network Plasticity Opens Novel Therapeutic Possibilities in Cancer, Diabetes, and Neurodegeneration.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Molecular and Immune Mechanisms Governing Cancer Metastasis, Including Dormancy, Microenvironmental Niches, and Tumor-Specific Programs.International journal of molecular sciences · 2026Review
- Perspective on the integration of radiomics and spatial omics in the analysis of the tumor microenvironment of bladder cancer and prospects for precision diagnosis and treatment.Frontiers in immunology · 2026Review
- Periostin Safeguards EGFR-Driven Genomic Instability and Sustains the Immune-Suppressive Niche in Glioblastoma.Human mutation · 2026Article
- Targeting immune microenvironment-mediated mesenchymal transition in glioblastoma: Molecular mechanisms and translational strategies.Neuro-oncology advancesReview
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Background: Glioblastoma (GBM) exhibits marked plasticity and intense microenvironmental crosstalk. We aimed to delineate mesenchymal programs with spatial resolution, clinical relevance, and mechanistic anchors. Methods: We integrated single-cell RNA-seq, bulk transcriptomes, and Visium spatial data. After rigorous QC and Harmony integration, we annotated 12 cell states using canonical markers, decoupler-based ORA, and AUCell. Tumor boundaries were defined by inferCNV/CopyKAT; developmental potential by CytoTRACE2 and PHATE. Post-translational modification (PTM) axes were scored from curated gene sets. A cell type-aware GNN linked bulk expression to a patient-similarity graph for survival modeling and gene-level hazard attribution. Network convergence combined bulk WGCNA (TCGA/CGGA), single-cell hdWGCNA, BayesPrism deconvolution, and external GEO validation. Ligand-receptor (LR) signaling was inferred with LIANA+, embedded in a signed causal network, and mapped spatially. ARRDC3 expression was assessed in GBM tissues; U251 gain- and loss-of-function assays evaluated proliferation and migration. Results: We resolved major GBM states, including two mesenchymal programs (MES1-like, MES2-like). CNV-high regions marked malignant cores, and CytoTRACE2 identified high-potency niches within MES2-like and Proliferation states along non-linear trajectories. PTM landscapes segregated by state; S-nitrosylation, glycosylation, and lactylation were enriched in mesenchymal programs. A GNN risk score stratified overall survival in TCGA (n=157) and generalized to CGGA-325 (n=85) and CGGA-693 (n=140). MES2-like abundance remained an independent adverse predictor (HR = 2.31; 95% CI, 1.04-5.10). MES2-high tumors upregulated EMT, TNFα/NF-κB, JAK/STAT, hypoxia, angiogenesis, and glycolysis; S-nitrosylation associated with increased hazard. Cross-modal convergence defined a conservative MES2 core enriched for ECM remodeling, collagen modification, focal adhesion, and TGF-β regulation. LR analysis prioritized a TAM-to-MES2 axis (e.g., GRN-TNFRSF1A, ADAM9/10/17-ITGB1, TGFB1-ITGB1/EGFR) converging on a CEBPD-centered module. Spatial mapping localized MES2 hotspots within CNV-defined territories and revealed a TNFRSF1A-CEBPD-ARRDC3 focus at an infiltrative rim. ARRDC3 was upregulated in GBM tissues; in U251 cells, knockdown promoted and overexpression suppressed proliferation and migration, indicating context-dependent roles. Conclusions: MES2-like GBM is an ECM-driven, stress-adapted state with strong prognostic impact. We nominate CEBPD and TNFRSF1A/ITGB1 as actionable nodes and identify ARRDC3 as a spatially restricted effector with context-dependent tumor-modulatory functions warranting therapeutic exploration.
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