Yang Yang, Tang Xinqiao, Liu Zhong
Department of Orthopedic Surgery, Xiangtan Central Hospital, Xiangtan, Hunan, P.R. China.
Xiangtan Central Hospital, Xiangtan, Hunan, P.R. China.
Technol Cancer Res Treat. 2025 Jan-Dec;24:15330338251336275. doi: 10.1177/15330338251336275. Epub 2025 Apr 17.
IntroductionOsteosarcoma (OS) is a highly aggressive primary bone malignancy with poor prognosis. Histone modifications play crucial roles in tumor progression, but their systematic investigation in OS remains unexplored.MethodsThis study integrated single-cell RNA sequencing data and large-scale clinical information to systematically analyze the spatial heterogeneity of histone modifications in OS and their clinical significance. We employed Seurat for single-cell data analysis, CellChat for cell-cell communication network analysis, and LASSO Cox regression to construct a prognostic model. Additionally, we conducted functional enrichment analysis, immune characteristics analysis, and drug sensitivity prediction.ResultsWe identified five major cell types in the OS microenvironment and discovered significant differences in histone modification levels among different cell types, with osteosarcoma cells and endothelial cells exhibiting higher modification levels. Cell-cell communication network analysis revealed the importance of signaling pathways such as SPP1, CypA, MIF, IGFBP, and VEGF in OS. Based on nine histone modification-related genes, we constructed an efficient prognostic model (AUC values of 0.713, 0.845, and 0.888 for 1-, 3-, and 5-year predictions, respectively), which was validated in an external cohort (AUC = 0.808). Immune microenvironment analysis showed significantly higher proportions of CD8+ T cells and Treg cells in the low-risk group. Drug sensitivity analysis revealed that the low-risk group was more sensitive to Imatinib, Rapamycin, and Sunitinib, while the high-risk group was more sensitive to MAPK pathway inhibitors.ConclusionThis study systematically revealed the spatial heterogeneity of histone modifications in OS and their clinical significance for the first time, proposing an "epigenetic-immune" regulatory network hypothesis and developing a histone modification-based prognostic model. Our proposed "epigenetic-guided personalized medication strategy" provides new insights for precision treatment of OS, potentially significantly improving patient prognosis.
引言
骨肉瘤（OS）是一种侵袭性很强的原发性骨恶性肿瘤，预后较差。组蛋白修饰在肿瘤进展中起关键作用，但在骨肉瘤中的系统研究仍未开展。
方法
本研究整合单细胞RNA测序数据和大规模临床信息，系统分析骨肉瘤中组蛋白修饰的空间异质性及其临床意义。我们使用Seurat进行单细胞数据分析，CellChat进行细胞间通信网络分析，并使用LASSO Cox回归构建预后模型。此外，我们还进行了功能富集分析、免疫特征分析和药物敏感性预测。
结果
我们在骨肉瘤微环境中鉴定出五种主要细胞类型，并发现不同细胞类型之间组蛋白修饰水平存在显著差异，骨肉瘤细胞和内皮细胞的修饰水平较高。细胞间通信网络分析揭示了SPP1、CypA、MIF、IGFBP和VEGF等信号通路在骨肉瘤中的重要性。基于九个与组蛋白修饰相关的基因，我们构建了一个有效的预后模型（1年、3年和5年预测的AUC值分别为0.713、0.845和0.888），并在外部队列中得到验证（AUC = 0.808）。免疫微环境分析显示，低风险组中CD8 + T细胞和Treg细胞的比例显著更高。药物敏感性分析表明，低风险组对伊马替尼、雷帕霉素和舒尼替尼更敏感，而高风险组对MAPK通路抑制剂更敏感。
结论
本研究首次系统揭示了骨肉瘤中组蛋白修饰的空间异质性及其临床意义，提出了“表观遗传 - 免疫”调控网络假说，并开发了基于组蛋白修饰的预后模型。我们提出的“表观遗传指导的个性化用药策略”为骨肉瘤的精准治疗提供了新见解，有望显著改善患者预后。
