Bladder Cancer‐Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP‐Related Metabolic Reprogramming and SerRS O‐GlcNAcylation in Endothelial Cells

Abstract 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 α 5‐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.