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 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.

Identification of endothelial-related molecular subtypes for bladder cancer patients

“…When stimulated by BC cell-derived small extracellular vesicles, endothelial cells can enhance O-GlcNAcylation to promote angiogenesis in BC tissues ( 26 ). Furthermore, endothelial cells can be activated by interleukin (IL)-1 to facilitate BC progression and dissemination ( 27 ).…”

The interplay between the tumor microenvironment and tumor-derived small extracellular vesicles in cancer development and therapeutic response

“…They proposed inhibiting sEV-mediated GFAT1 secretion and targeting seryl-tRNA synthetase (SerRS) O-GlcNAcylation in ECs as potential strategies for antiangiogenic therapy in BCa. 124 Moreover, TDSEVs contribute to metabolic reprogramming and remodeling of the microenvironment, exacerbating tumor angiogenesis and drug resistance. Among angiogenic factors such as proteins and nucleic acids, TDSEVs induce changes in ECs, augmenting their proliferation, migration, and angiogenic potential.…”

Tumor-derived hypoxic small extracellular vesicles promote endothelial cell migration and tube formation via ALS2/Rab5/β-catenin signaling

“…Besides the welldescribed direct effects of hypoxia in endothelial cells, indirect mediators of angiogenesis induced by hypoxia remain poorly understood. Increasing evidence indicates that extracellular vesicles (EVs) liberated by tumor cells induce endothelial cell events associated with angiogenesis (6)(7)(8)(9)(10)(11) and, most importantly, that these events are further increased under hypoxic conditions (12)(13)(14)(15). Specifically, EVs derived from hypoxic tumor cells, including multiple myeloma, oral squamous cell carcinoma, colorectal, leukemia, and lung cancer, among others, induce endothelial cell migration and angiogenesis in vitro, when compared with their counterpart released in normoxic conditions (15)(16)(17)(18)(19).…”