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Updated: May 8, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Single-cell dissection of PTM-related networks reveals an immunosuppressed osteosarcoma ecosystem
Jingyu Chen1, Wei Zhang1, Hai Yan1
1The Second Affiliated Hospital of Nantong University, Nantong, China.
Background:
Osteosarcoma remains lethal for many patients with metastatic or relapsed disease. Post-translational modifications (PTMs) regulate protein signaling and may shape the tumor microenvironment and clinical behavior in osteosarcoma, but PTM-anchored transcriptomic programs are as yet not well defined.
Methods:
We integrated single-cell RNA sequencing from GSE162454 with curated PTM and immune gene sets to build a PTM-related framework for osteosarcoma. Tumor cell differentially expressed genes were intersected with PTM and immune repertoires to derive candidates. A PTM-related prognostic score was trained in TARGET-OS and validated in GSE21257 and GSE16091. Immune infiltration and microenvironment features were profiled using ssGSEA, Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE) data, and Tumor Immune Dysfunction and Exclusion (TIDE) scores. Model interpretation used SHapley Additive exPlanations (SHAP) and single-cell localization. GRN was prioritized for exploration of immune correlations and in vitro loss-of-function assays in U2OS and HOS cells.
Results:
The three-way intersection yielded 298 genes. The PTM-related score stratified overall survival in training and validation cohorts and remained independent of clinical covariates. High scores aligned with an immunosuppressed, stroma-rich microenvironment, with lower ImmuneScores and ESTIMATE scores, enrichment of myeloid and regulatory lineages, higher dysfunction and exclusion by TIDE, and reduced cytolytic, interferon, and antigen-presentation programs. SHAP highlighted a compact driver set enriched in malignant and stromal compartments. GRN showed strong contribution and consistent single-cell localization. Elevated GRN correlated with plasmacytoid dendritic cells, myeloid-derived suppressor cells (MDSCs), macrophages, regulatory T cells (Tregs), and multiple inhibitory checkpoints and with diminished immune effector functions. GRN silencing reduced proliferation, clonogenicity, migration, and invasion in osteosarcoma cells.
Conclusion:
A PTM-anchored transcriptomic signature captures prognostic heterogeneity in osteosarcoma and links adverse outcome to an immunosuppressed microenvironment. GRN emerges as a tumor- and stroma-intrinsic mediator of immune suppression and malignant traits and represents a biologically grounded target for future mechanistic and therapeutic studies.
Insights
A new PTM-anchored transcriptomic signature identifies osteosarcoma patients with poor prognosis. This signature correlates with an immunosuppressed tumor microenvironment and highlights GRN as a potential therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Osteosarcoma (OS) poses a significant threat to patients with metastatic or relapsed disease.
- Post-translational modifications (PTMs) influence protein signaling, potentially affecting the OS tumor microenvironment and clinical outcomes.
- PTM-driven transcriptomic programs in OS remain poorly understood.
Purpose of the Study:
- To develop a PTM-related transcriptomic framework for osteosarcoma.
- To identify prognostic biomarkers and understand their link to the tumor microenvironment.
- To explore the role of specific genes, like GRN, in OS progression and immune suppression.
Main Methods:
- Integration of single-cell RNA sequencing data with curated PTM and immune gene sets.
- Differential gene expression analysis intersected with PTM and immune repertoires.
- Development and validation of a PTM-related prognostic score using independent cohorts.
- Profiling of immune infiltration and microenvironment using ssGSEA, ESTIMATE, and TIDE.
- Model interpretation via SHAP and single-cell localization, with GRN investigation through in vitro assays.
Main Results:
- A PTM-related score stratified overall survival in OS patients, independent of clinical factors.
- High PTM scores correlated with an immunosuppressed, stroma-rich microenvironment, characterized by reduced immune scores and effector functions.
- SHAP analysis identified a core set of driver genes, with GRN showing significant contribution and localization within malignant and stromal compartments.
- Elevated GRN expression was associated with specific immune cell populations (e.g., MDSCs, Tregs) and inhibitory checkpoints, and reduced immune effector functions.
- GRN silencing inhibited osteosarcoma cell proliferation, clonogenicity, migration, and invasion.
Conclusions:
- A PTM-anchored transcriptomic signature effectively captures prognostic heterogeneity in osteosarcoma.
- This signature links adverse outcomes to an immunosuppressed tumor microenvironment.
- GRN acts as an intrinsic mediator of immune suppression and malignant traits in OS, presenting a promising target for future therapeutic strategies.
