Transl Cancer Res. 2026 Jan 31;15(1):43. doi: 10.21037/tcr-2025-1499. Epub 2026 Jan 27.

ABSTRACT

BACKGROUND: Osteoglycin (OGN), an extracellular matrix protein, has emerging but poorly characterized roles in cancer. This study presents the first pan-cancer investigation of OGN's expression patterns, clinical significance, immune interactions, and functional mechanisms.

METHODS: Multi-omics data from Genotype Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA), and Human Protein Atlas (HPA) databases were integrated. Differential expression was analyzed in normal tissues and tumor samples. Diagnostic utility was evaluated using area under the curve (AUC) of receiver operating characteristic (ROC) curve. Prognostic value was assessed via Kaplan-Meier [overall survival (OS); disease-specific survival (DSS); disease free interval (DFI); progression-free interval (PFI)] and Cox regression analyses. Immune microenvironment correlations were quantified using ESTIMATE, CIBERSORT, and gene set enrichment. Functional pathways were explored through gene set enrichment analysis (GSEA) and correlation with hallmark cancer signatures.

RESULTS: OGN was broadly expressed in normal tissues (brain, liver, kidney) but significantly downregulated in most tumor types (P<0.05, TCGA; validated at protein level, HPA). OGN demonstrated high diagnostic accuracy in pan-cancer (AUC: 0.703-0.990), achieving near-perfect performance in colon adenocarcinoma (COAD) (AUC: 0.966) and thyroid cancer (THCA) (AUC: 0.920). High OGN expression correlated with improved survival outcomes in thymoma (THYM) (OS/DSS) and cholangiocarcinoma (CHOL) (PFI/DFI), but worse prognosis in lung adenocarcinoma​/liver hepatocellular carcinoma​ (LUAD/LIHC), indicating cancer-type specificity. OGN expression strongly associated with immune cell infiltration (macrophages, natural killer cells, T cells), chemokine signaling, programmed death-ligand 1 (PD-L1) levels, microsatellite instability (MSI), and tumor mutation burden (TMB). GSEA revealed enrichment of OGN-linked genes in epithelial-mesenchymal transition (EMT), angiogenesis, JAK-STAT, and PI3K pathways across cancers.

CONCLUSIONS: Our pan-cancer analysis highlights OGN as a context-dependent regulator linking extracellular matrix (ECM) remodeling with immune and angiogenic signaling. Its pan-cancer dysregulation, diagnostic/prognostic value, and crosstalk with immune evasion mechanisms nominate OGN as a promising multi-functional biomarker and therapeutic target.

PMID:41674945 | PMC:PMC12885879 | DOI:10.21037/tcr-2025-1499

Nat Commun. 2025 Aug 22;16(1):7827. doi: 10.1038/s41467-025-63146-2.

ABSTRACT

While dysregulation of polyamine metabolism is frequently observed in cancer, it is unknown how polyamines alter the tumor microenvironment (TME) and contribute to therapeutic resistance. Analysis of polyamines in the plasma of pancreatic cancer patients reveals that spermine levels are significantly elevated and correlate with poor prognosis. Using a multi-omics approach, we identify Serpinb9 as a vulnerability in spermine metabolism in pancreatic cancer. Serpinb9, a serine protease inhibitor, directly interacts with spermine synthase (SMS), impeding its lysosome-mediated degradation and thereby augmenting spermine production and secretion. Mechanistically, the accumulation of spermine in the TME alters the metabolic landscape of immune cells, promoting CD8⁺ T cell dysfunction and pro-tumor polarization of macrophages, thus creating an immunosuppressive microenvironment. Small peptides that disrupt the Serpinb9-SMS interaction significantly enhance the efficacy of immune checkpoint blockade therapy. Together, our findings suggest that targeting spermine metabolism is a promising strategy to improve pancreatic cancer immunotherapy.

PMID:40846845 | PMC:PMC12373741 | DOI:10.1038/s41467-025-63146-2

Cell Metab. 2025 Jan 28:S1550-4131(24)00495-9. doi: 10.1016/j.cmet.2024.12.013. Online ahead of print.

ABSTRACT

Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment but remains effective in only a subset of patients. Emerging evidence suggests that the gut microbiome and its metabolites critically influence ICB efficacy. In this study, we performed a multi-omics analysis of fecal microbiomes and metabolomes from 165 patients undergoing anti-programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) therapy, identifying microbial and metabolic entities associated with treatment response. Integration of data from four public metagenomic datasets (n = 568) uncovered cross-cohort microbial and metabolic signatures, validated in an independent cohort (n = 138). An integrated predictive model incorporating these features demonstrated robust performance. Notably, we characterized five response-associated enterotypes, each linked to specific bacterial taxa and metabolites. Among these, the metabolite phenylacetylglutamine (PAGln) was negatively correlated with response and shown to attenuate anti-PD-1 efficacy in vivo. This study sheds light on the interplay among the gut microbiome, the gut metabolome, and immunotherapy response, identifying potential biomarkers to improve treatment outcomes.

PMID:39909032 | DOI:10.1016/j.cmet.2024.12.013