Glypican-3 regulated epithelial mesenchymal transformationrelated genes in osteosarcoma: based on comprehensive tumor microenvironment profiling

Jiaming Zhang¹Wei Wang^2*

• ¹Cancer Hospital of Dalian University of Technology, Liaoning cancer Hospital&Institute Department of Bone and Soft Tissue Tumor Surgery, Dalian, China
• ²Department of Bone and Soft Tissue Tumor Surgery, Shenyang, China

Osteosarcoma (OS) is the most common primary bone malignancy, and mainly affects children and adolescents. The current treatment approaches for OS have limited efficacy, and the 5-year survival rate is roughly 60%. Epithelial-mesenchymal transition (EMT) plays a key role in the onset, progression, and metastasis of OS, and may influence patient prognosis. In this study, we screened EMT-related genes from multiple transcriptomic datasets of OS, and performed unsupervised consensus clustering of EMT-related gene sets. The key genes related to EMT were identified by weighted gene co-expression network analysis (WGCNA), and intersected with the differentially expressed genes (DEGs) between OS and normal tissue samples. The least absolute shrinkage and selection operator (LASSO) algorithm was then used to screen candidate genes for developing a prognostic model. The predictive capacity of the EMT-based model was validated across several cohorts. Furthermore, the prognostic model also predicted immune-related features and immunotherapy responses in the high-risk and low-risk groups. We identified seven primary cell types from the scRNA-Seq data of OS samples, and found that the osteoblast population had the highest proportion of cells positive for the model genes. The OS_C3 subpopulation had significantly higher scores, and included nine gene modules associated with metabolism, structural integrity, proliferation, differentiation, adhesion, migration, immune responses, inflammatory reactions, and signal transduction. The model genes also showed prognostic value across various cancer types. Finally, the proliferation and migration ability were decrease after si-GPC3 in MG-63 cell line, In conclusion, this study provides new insights into the potential mechanisms of EMT in OS, and its impact on the tumor immune microenvironment and response to immunotherapy, which can pave the way for novel personalized treatment strategies.