葡萄膜黑色素瘤（UM）是最常见的成人眼内肿瘤，其特点是恶性程度高，晚期预后差。血管生成对于 UM 的发展至关重要，然而，不仅血管内皮功能障碍在 UM 中的作用仍不清楚，而且还缺乏在单细胞水平上的分析。全面的分析对于阐明内皮在UM发生发展中的作用至关重要。我们利用11例原发性和肝转移性UM的单细胞RNA转录组数据，分析了内皮细胞的状态。此外，我们在体外模型中分析和验证了 EC，并收集了临床标本。随后，我们探讨了内皮功能障碍对UM细胞迁移的影响，并探讨了内皮细胞异常的机制及其外周效应的原因。与原位肿瘤相比，UM转移瘤中血管内皮细胞的比例显着更高，并且内皮细胞的比例显着高于原位肿瘤。转移中的细胞表现出明显的衰老。转移性肿瘤中的衰老内皮细胞表现出显着的Krüppel样因子4（KLF4）上调，正常内皮细胞中KLF4的过度表达诱导衰老，而衰老内皮细胞中KLF4的敲低则抑制衰老，表明KLF4是内皮衰老的驱动基因。 KLF4诱导的内皮衰老通过衰老相关分泌表型（SASP）驱动肿瘤细胞迁移，其中效应子最重要的成分是CXCL12（C-X-C基序趋化因子配体12），并参与免疫抑制微环境的组成。研究提供了关于衰老内皮细胞促进 UM 转移的不良见解。© 2024。作者。

Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM.By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects.UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment.This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.© 2024. The Author(s).