Zhang Jiaming, Wang Wei
Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital and Institute, Liaoning, Shenyang, China.
Front Immunol. 2025 May 13;16:1566061. doi: 10.3389/fimmu.2025.1566061. eCollection 2025.
Osteosarcoma (OS) is the most common primary bone malignancy, predominantly affecting children and adolescents. Current treatment approaches have limited efficacy, with a 5-year survival rate of approximately 60%. Epithelial-mesenchymal transition (EMT) plays a key role in the onset, progression, and metastasis of OS, potentially influencing patient prognosis.
We screened EMT-related genes from multiple transcriptomic datasets of OS and performed unsupervised consensus clustering of EMT-related gene sets. Key EMT-related genes were identified using weighted gene co-expression network analysis (WGCNA) and intersected with differentially expressed genes (DEGs) between OS and normal tissue samples. The least absolute shrinkage and selection operator (LASSO) algorithm was applied to screen candidate genes for developing a prognostic model. Single-cell RNA-Seq (scRNA-Seq) analysis was conducted on OS samples to identify cell populations expressing model genes. Functional validation was performed using si-GPC3 in the MG-63 cell line.
The EMT-based prognostic model demonstrated strong predictive capacity across several validation cohorts. The model effectively predicted immune-related features and immunotherapy responses in high-risk and low-risk patient groups. Seven primary cell types were identified from scRNA-Seq data of OS samples, with the osteoblast population showing the highest proportion of cells positive for model genes. The OS_C3 subpopulation exhibited 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 demonstrated prognostic value across various cancer types. Knockdown of GPC3 in MG-63 cells resulted in decreased proliferation and migration ability.
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. These findings may pave the way for novel personalized treatment strategies for OS patients.
骨肉瘤（OS）是最常见的原发性骨恶性肿瘤，主要影响儿童和青少年。目前的治疗方法疗效有限，5年生存率约为60%。上皮-间质转化（EMT）在骨肉瘤的发生、发展和转移中起关键作用，可能影响患者预后。
我们从多个骨肉瘤转录组数据集中筛选EMT相关基因，并对EMT相关基因集进行无监督一致性聚类。使用加权基因共表达网络分析（WGCNA）鉴定关键的EMT相关基因，并与骨肉瘤和正常组织样本之间的差异表达基因（DEG）进行交集分析。应用最小绝对收缩和选择算子（LASSO）算法筛选用于建立预后模型的候选基因。对骨肉瘤样本进行单细胞RNA测序（scRNA-Seq）分析，以鉴定表达模型基因的细胞群体。在MG-63细胞系中使用si-GPC3进行功能验证。
基于EMT的预后模型在多个验证队列中显示出强大的预测能力。该模型有效地预测了高危和低危患者组的免疫相关特征和免疫治疗反应。从骨肉瘤样本的scRNA-Seq数据中鉴定出七种主要细胞类型，其中成骨细胞群体显示模型基因阳性细胞比例最高。OS_C3亚群表现出明显更高的评分，包括与代谢、结构完整性、增殖、分化、粘附、迁移、免疫反应、炎症反应和信号转导相关的九个基因模块。模型基因在各种癌症类型中也显示出预后价值。MG-63细胞中GPC3的敲低导致增殖和迁移能力下降。
本研究为骨肉瘤中EMT的潜在机制及其对肿瘤免疫微环境和免疫治疗反应的影响提供了新的见解。这些发现可能为骨肉瘤患者的新型个性化治疗策略铺平道路。
