重庆医科大学附属第一医院泌尿外科科研团队首次发现驱动膀胱癌血管生成的新机制，为晚期膀胱癌的靶向治疗提供了新靶点。该成果"Bladder Cancer-Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP-Related Metabolic Reprogramming and SerRS O-GlcNAcylation in Endothelial Cells"发表在国际著名期刊Advanced Science上。这也是该研究团队在膀胱癌肿瘤微环境领域的又一篇高影响力的文章。该研究成果被国家卫健委主管报刊《健康报》报道。

    多年来，重医附一院泌尿外科科研团队依托医院科研平台，致力于膀胱癌发生发展及其微环境的探索，以期发现新的治疗靶点。经过长期的研究探索，目前已形成较为成熟的研究体系。最近，团队首次发现在缺乏营养的肿瘤微环境中，膀胱癌细胞和肿瘤相关血管内皮细胞之间存在一种新的代谢关联，即依赖于膀胱癌细胞分泌的小细胞外囊泡作为媒介传递氨基己糖生物合成途径的关键限速酶——GFAT1。它作为一个关键的代谢开关，通过增加内皮细胞中氨基己糖生物合成途径的通量，实现葡萄糖代谢重编程，从而促进膀胱癌血管生成。该研究结果提示，抑制膀胱癌细胞以小细胞外囊泡为媒介分泌GFAT1以及调控肿瘤微环境中血管内皮细胞的葡萄糖代谢程序，都可能成为靶向膀胱癌血管生成治疗的新策略。

    该研究的通讯作者是苟欣教授，第一作者是李心远博士。

    摘要：A malformed tumour vascular network provokes the nutrient-deprived tumour microenvironment (TME), which conversely activates endothelial cell (EC) functions and stimulates neovascularization. Emerging evidence suggests that the flexible metabolic adaptability of tumour cells helps to establish a metabolic symbiosis among various cell subpopulations in the fluctuating TME. In this study, the authors propose a novel metabolic link between bladder cancer (BCa) cells and ECs in the nutrient-scarce TME, in which BCa-secreted glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1) via small extracellular vesicles (sEVs) reprograms glucose metabolism by increasing hexosamine biosynthesis pathway flux in ECs and thus enhances O-GlcNAcylation. Moreover, seryl-tRNA synthetase (SerRS) O-GlcNAcylation at serine 101 in ECs promotes its degradation by ubiquitination and impeded importin α5-mediated nuclear translocation. Intranuclear SerRS attenuates vascular endothelial growth factor transcription by competitively binding to the GC-rich region of the proximal promotor. Additionally, GFAT1 knockout in tumour cells blocks SerRS O-GlcNAcylation in ECs and attenuates angiogenesis both in vitro and in vivo. However, administration of GFAT1-overexpressing BCa cells-derived sEVs increase the angiogenetic activity in the ECs of GFAT1-knockout mice. In summary, this study suggests that inhibiting sEV-mediated GFAT1 secretion from BCa cells and targeting SerRS O-GlcNAcylation in ECs may serve as novel strategies for BCa antiangiogenetic therapy.

    畸形的肿瘤血管网络会引发营养缺乏的肿瘤微环境(TME)，进而激活内皮细胞(EC)功能并刺激新血管形成。新出现的证据表明，肿瘤细胞灵活的代谢适应性有助于在波动的TME中建立各种细胞亚群之间的代谢共生关系。在这项研究中，作者提出了营养缺乏的TME中膀胱癌(BCa)细胞和ECs之间的新代谢联系，其中BCa通过小的细胞外囊泡(sEVs)分泌谷氨酰胺-果糖-6-磷酸转氨酶1(GFAT1))通过增加ECs中的己糖胺生物合成途径通量来重新编程葡萄糖代谢，从而增强O-GlcNAc糖基化修饰（O-GlcNAcylation）。此外，ECs中丝氨酸101处的丝氨酰-tRNA合成酶(SerRS)的O-GlcNAc修饰促进其通过泛素化降解并阻碍输入蛋白α5介导的核转位。核内SerRS通过与近端启动子的富含GC的区域竞争性结合来减弱血管内皮生长因子的转录。而肿瘤细胞中的GFAT1敲除阻断了ECs中的SerRS蛋白的O-GlcNAc修饰，并在体外和体内减弱了血管生成。然而，施用过表达GFAT1的BCa细胞衍生的sEV会增加GFAT1敲除小鼠EC中的血管生成活性。总之，这项研究表明，抑制sEV介导的BCa细胞分泌GFAT1并靶向ECs中的SerRS的O-GlcNAc修饰可作为BCa抗血管生成治疗的新策略。

    关键词: O-GlcNAcylation; angiogenesis; glutamine-fructose-6-phosphate aminotransferase 1; metabolic reprogramming; small extracellular vesicles. 

    原文：https://pubmed.ncbi.nlm.nih.gov/36045101/ 

   参考文献： Li, X., Peng, X., Zhang, C., Bai, X., Li, Y., Chen, G., Guo, H., He, W., Zhou, X., & Gou, X. (2022). Bladder Cancer-Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP-Related Metabolic Reprogramming and SerRS O-GlcNAcylation in Endothelial Cells. Advanced science , e2202993. https://doi.org/10.1002/advs.202202993