Integrated multi-omics profiling identifies ECM-associated and systemic metabolic alterations associated with osteosarcoma metastasis

Introduction Osteosarcoma metastasis remains a major clinical challenge, and the molecular programs underlying metastatic progression across omics layers are still incompletely understood. Methods We established an orthotopic osteosarcoma metastasis model using fluorescence-labeled 143B cells and performed integrated transcriptomic, proteomic, and serum metabolomic profiling. Multi-omics integration identified cross-layer RNA-protein-metabolite associations and prioritized hub molecules, including COL1A2, SPARC, ATP1A2, ACTA1, and MPZ. Public validation in TARGET-OS and GSE21257 supported a conserved hub/ECM co-expression module across independent cohorts. Functional assays evaluated the role of COL1A2 in osteosarcoma cell proliferation, migration, and invasion. Results Histological examination confirmed lung metastatic lesions in 6/6 metastasis-bearing mice but not in non-metastatic controls. Transcriptomic and proteomic profiling revealed concurrent ECM remodeling and metabolic pathway alterations. Multi-omics integration identified 32 consistently altered molecules across all three omics layers. COL1A2 was prioritized as a key hub molecule. COL1A2 knockdown promoted, whereas COL1A2 overexpression suppressed, osteosarcoma cell proliferation, migration, and Transwell invasion. Rescue experiments confirmed COL1A2-dependent regulation of these malignant phenotypes. Conclusion These findings reveal concurrent ECM remodeling and systemic metabolic alterations associated with osteosarcoma metastasis and identify COL1A2 as a functionally relevant ECM-associated hub molecule that may serve as a potential therapeutic target.