Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, 200040, P.R. China.
Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, P.R. China.
J Cancer Res Clin Oncol. 2024 Nov 6;150(11):487. doi: 10.1007/s00432-024-06017-5.
Highly complex tumor microenvironment makes hepatocellular carcinoma (HCC) as one of the most malignant tumors worldwide. The role of cellular senescence in HCC has been gradually recognized. The present study aimed to comprehensively elucidate the senescence-related features of HCC in single-cell and spatial dimension.
Single-cell RNA sequencing (scRNA-Seq) data was used to clarify the heterogeneity of senescence-related genes (SRGs) among multiple cell types within HCC. Spatial transcriptome RNA sequencing (stRNA-Seq) data was used for depicting SRGs features in spatial dimension. A prognostic model based on SRGs was constructed by using of bulk sequencing (bulk-Seq) data of HCC. The cell-cell interaction of senescent endothelial cells (ECs) in tumor microenvironment was analyzed. Then, the role of senescent ECs was verified through in vitro and in vivo experiments.
The level of senescence demonstrated substantial heterogeneity among different cell types within tumor microenvironment of HCC, where ECs exhibited the most prominent senescent phenotype. Senescent ECs activated specific regulatory pathways through communicating with other cell types, with a potential impact on tumor progression. Spatial analysis revealed senescent ECs mainly located in the core region of HCC. The interaction of senescent ECs and immune cells implicated their role in tumor progression and immunotherapeutic response. In addition, CDKN2A was identified as an independent risk factor for HCC prognosis by constructing a prognostic model. Patients with high risk displayed an even worse outcome. The experimental verification indicated senescence of ECs determined by CDKN2A exhibited a secretory phenotype. Furthermore, senescent ECs with CDKN2A overexpression promote the proliferation and migration of HCC.
The present study recognizes the critical effect of senescent ECs defined by CDKN2A in the promotion of tumor progression, which sheds new light on the investigation of ECs senescence in HCC.
高度复杂的肿瘤微环境使肝细胞癌（HCC）成为全球最恶性的肿瘤之一。细胞衰老在 HCC 中的作用逐渐被认识。本研究旨在全面阐明 HCC 在单细胞和空间维度上与衰老相关的特征。
使用单细胞 RNA 测序（scRNA-Seq）数据阐明 HCC 中多种细胞类型中与衰老相关基因（SRGs）的异质性。使用空间转录组 RNA 测序（stRNA-Seq）数据描绘 SRGs 在空间维度上的特征。使用 HCC 的批量测序（bulk-Seq）数据构建基于 SRGs 的预后模型。分析肿瘤微环境中衰老内皮细胞（ECs）的细胞间相互作用。然后，通过体外和体内实验验证衰老 ECs 的作用。
衰老表型在 HCC 肿瘤微环境中的不同细胞类型之间存在显著异质性，其中 ECs 表现出最显著的衰老表型。衰老的 ECs 通过与其他细胞类型相互作用激活特定的调控途径，对肿瘤进展具有潜在影响。空间分析显示衰老的 ECs主要位于 HCC 的核心区域。衰老 ECs 与免疫细胞的相互作用表明它们在肿瘤进展和免疫治疗反应中的作用。此外，通过构建预后模型，发现 CDKN2A 可作为 HCC 预后的独立危险因素。高风险患者的预后更差。实验验证表明，由 CDKN2A 确定的 ECs 衰老表现出分泌表型。此外，CDKN2A 过表达的衰老 ECs促进 HCC 的增殖和迁移。
本研究认识到由 CDKN2A 定义的衰老 ECs 在促进肿瘤进展中的关键作用，为研究 HCC 中 ECs 衰老提供了新的视角。
