Wei Zhi-Qiang, Ding Sheng, Yang Yan-Cai
The Department of Pediatric Surgery, The Ningbo Women and Children's Hospital, Ningbo, China.
Front Oncol. 2023 May 3;13:1200203. doi: 10.3389/fonc.2023.1200203. eCollection 2023.
Endothelial cells (ECs) play a vital role in promoting the progression of malignant cells, and they exhibit heterogeneity in their phenotypic characteristics. We aimed to explore the initiating cells of ECs in osteosarcoma (OS) and investigate their potential interaction with malignant cells.
We obtained scRNA-seq data from 6 OS patients, and datasets were batch-corrected to minimize variations among samples. Pseudotime analysis was performed to investigate the origin of differentiation of ECs. CellChat was employed to examine the potential communication between endothelial cells and malignant cells, and gene regulatory network analysis was performed to identify transcription factor activity changes during the conversion process. Importantly, we generated TYROBP-positive ECs and investigated its role in OS cell lines. Finally, we explored the prognosis of specific ECs cluster and their impact on the tumor microenvironment (TME) at the bulk transcriptome level.
The results showed that TYROBP-positive ECs may play a crucial role in initiating the differentiation of ECs. TYROBOP-positive endothelial cells (ECs) exhibited the strongest crosstalk with malignant cells, likely mediated by TWEAK, a multifunctional cytokine. TYROBP-positive ECs exhibited significant expression of TME-related genes, unique metabolic and immunological profiles. Importantly, OS patients with low enrichment of TYROBP-positive ECs had better prognoses and a lower risk of metastasis. Finally, vitro assays confirmed that TWEAK was significantly increased in ECs-conditioned medium (ECs-CM) when TYROBP was over-expressed in EC cells, and could promote the proliferation and migration of OS cells.
We concluded that TYROBP-positive ECs may be the initiating cells and play a crucial role in the promotion of malignant cell progression. TYROBP-positive ECs have a unique metabolic and immunological profile and may interact with malignant cells through the secretion of TWEAK.
内皮细胞（ECs）在促进恶性细胞进展中起重要作用，且其表型特征存在异质性。我们旨在探究骨肉瘤（OS）中内皮细胞的起始细胞，并研究它们与恶性细胞的潜在相互作用。
我们获取了6例骨肉瘤患者的单细胞RNA测序（scRNA-seq）数据，并对数据集进行批处理校正以最小化样本间差异。进行了拟时间分析以研究内皮细胞的分化起源。使用CellChat来检查内皮细胞与恶性细胞之间的潜在通讯，并进行基因调控网络分析以识别转化过程中转录因子活性的变化。重要的是，我们生成了酪氨酸蛋白（TYROBP）阳性的内皮细胞，并研究了其在骨肉瘤细胞系中的作用。最后，我们在批量转录组水平上探究了特定内皮细胞簇的预后及其对肿瘤微环境（TME）的影响。
结果表明，TYROBP阳性的内皮细胞可能在启动内皮细胞分化中起关键作用。TYROBOP阳性的内皮细胞与恶性细胞表现出最强的串扰，可能由多功能细胞因子肿瘤坏死因子样弱凋亡诱导因子（TWEAK）介导。TYROBP阳性的内皮细胞表现出与肿瘤微环境相关基因的显著表达、独特的代谢和免疫特征。重要的是，TYROBP阳性内皮细胞富集程度低的骨肉瘤患者预后较好且转移风险较低。最后，体外试验证实，当在内皮细胞中过表达TYROBP时，内皮细胞条件培养基（ECs-CM）中的TWEAK显著增加，并且可以促进骨肉瘤细胞的增殖和迁移。
我们得出结论，TYROBP阳性的内皮细胞可能是起始细胞，并在促进恶性细胞进展中起关键作用。TYROBP阳性的内皮细胞具有独特的代谢和免疫特征，并且可能通过分泌TWEAK与恶性细胞相互作用。
