PSAT1 drives extracellular vesicle release in multiple types of cancer and promotes bone metastasis by activating osteoclasts
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ABSTRACT:
PROVIDER: PRJNA768649 | ENA |
REPOSITORIES: ENA
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Project description:Cancer cells secrete extracellular vesicles (EVs) to regulate cells in the tumor microenvironment for their own benefit to grow and survive in the patient’s body. Although emerging evidence has demonstrated the molecular mechanisms of EV release, regulating cancer-specific EV secretion remains challenging . In this study, we applied a microRNA (miRNA) library to reveal the universal mechanisms of EV secretion in cancer cells. Here, we identified miR-891b and its direct target gene, phospho-aminotransferase 1 (PSAT1), which promotes EV secretion through the serine-ceramide synthesis pathway. Inhibition of PSAT1 affected EV secretion in multiple types of cancer, suggesting that the miR-891b/PSAT1 axis shares a common mechanism of cancer EV secretion.
2021-10-07 | GSE185312 | GEO
Project description:Oncogenes reprogram multiple metabolic phenotypes of cancer cells including the balance between anabolic and catabolic processes, mechanisms of nutrient uptake, and choices in nutrient utilization. Here, we explore how different oncogenes regulate biomass loss via extracellular vesicle release. We use isogenic mammary breast epithelial cells transformed with a panel of oncogenes found commonly mutated, amplified or overexpressed in multiple cancers. We observe an increase in extracellular vesicle (EV) release upon oncogenic transformation, with MYC and AURKB oncogenes eliciting the highest number of EVs produced. Oncogene expression altered the protein composition of released EVs. Likewise, miRNAs were differentially sorted into EVs in an oncogene-specific manner. We performed an integrated pathway analysis of metabolites and gene expression across different oncogene-expressing cells and identified that ceramide-sphingosine metabolism was broadly deregulated, especially in MYC overexpressing cells. Inhibition of neutral sphingomyelinases (N-SMase) resulted in significant decrease in EV production in MYC high cells, while ESCRT-dependent small EV production predominated in AURKB cells.
2020-05-06 | GSE130768 | GEO
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Project description:EVs were isolated from primary human aortic endothelial cells (ECs) (+/- IL-1b activation), quantified, and analysed by miRNA transcriptomics and proteomics. Compared to quiescent ECs, activated ECs increased EV release, with miRNA and protein cargo that were related to atherosclerosis pathways. RNA sequencing of EV-treated monocytes and vascular smooth muscle cells (VSMCs) revealed that EVs from activated ECs altered pathways that were pro-inflammatory and atherogenic.
2024-01-02 | GSE231715 | GEO
Project description:Liver fibrosis is characterized by the activation of hepatic stellate cells (HSCs) and the release of fibrogenic nano-sized extracellular vesicles (EVs). Activated HSCs increase their glucose metabolism via glycolysis to satisfy high energy demands. Nevertheless, the mechanism of how glycolysis in HSCs coordinates fibrosis amplification in the fibrogenic zones in the liver is elusive and is the scope of this study. Single cell RNA sequencing (scRNAseq) and bulk RNAseq demonstrated that several glycolysis enzymes, including hexokinase 2 (HK2), were upregulated in activated HSCs. HSC-selective glycolysis-deficient mice (HK2ΔHSC) showed abrogated CCl4-mediated fibrosis as compared to littermate controls (HK2fl/fl). Spatial transcriptomics revealed an upregulation of several EV-related pathways in the fibrotic pericentral zone during liver fibrosis in control HK2fl/fl mice. However, glycolysis-deficient HK2ΔHSC mice showed downregulation of these EV-related pathways in the pericentral zone. Consistently, induction of glycolysis in HSCs in vitro, either by glucose or platelet-derived growth factor B (PDGF), upregulated the expression of several extracellular vesicle (EV)-related genes, including RAB31. Glycolysis in HSCs epigenetically enhanced RAB31 expression through histone-3 lysine-9 acetylation (H3K9ac) on the promoter region, leading to increased EV release. Functionally, glycolysis-dependent EVs were enriched with fibrogenic molecules and increased the expression of fibrotic markers in recipient HSCs. Finally, EVs derived from glycolysis-deficient HK2ΔHSC mice abrogated liver fibrosis amplification as compared to EVs derived from littermate control HK2fl/fl mice. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the pericentral fibrotic regions in the liver.
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Project description:The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signaling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the non-selective S1P receptor agonist FTY720 causes increased bone formation in wildtype, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo, and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts. Osteoclasts of wildtype and Calcr-/- C57Bl/6 mice were treated with Calcitonin and compared to the non-treated osteoclasts of wildtype or Calcr-/- mice, respectively.
2014-10-19 | E-GEOD-60761 | biostudies-arrayexpress
Project description:Mycobacterium tuberculosis (Mtb) secretes pathogenicity factors and immunologically active molecules via membrane vesicles. However, nothing is known about the mechanisms involved in mycobacterial vesicle biogenesis. This study investigates molecular determinants of membrane vesicle production in Mtb by analyzing Mtb cells under conditions of high vesicle production: iron limitation and VirR restriction. Ultrastructural analysis showed extensive cell envelope restructuring in association with vesicle release that correlated with downregulation of cell surface lipid biosynthesis and peptidoglycan alterations. Comparative transcriptomics showed common upregulation of the iniBAC operon in association with high vesicle production in Mtb cells. Vesicle production analysis demonstrated that the dynamin-like proteins (DLPs) encoded by this operon, IniA and IniC, are necessary for release of EV by Mtb in culture and in infected macrophages. Isoniazid, a first-line antibiotic, used in tuberculosis treatment, was found to stimulate vesicle release in a DLP-dependent manner. Our results provide a new understanding of the function of mycobacterial DLPs and mechanistic insights into vesicle biogenesis. The findings will enable further understanding of the relevance of Mtb-derived extracellular vesicles in the pathogenesis of tuberculosis and may open new avenues for therapeutic research.
2023-06-22 | GSE143996 | GEO
Project description:Comparison of goat and cow milk-derived extracellular vesicle miRNomes (microRNA expression profiles) determined usiing RNA-sequencing (NGS).
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Project description:We report the application of a novel integrated screening strategy to identify lncRNAs that regulate synaptic vesicle release. We identified one of these lncRNAs, which is conserved across mammals, neuron-specific and strictly nuclear. Modulations of this lncRNA influence synaptic vesicle release, presynaptic calcium influx, neurite elongation and neuronal migration. We have characterized the DNA, RNA and protein inteactors of this lncRNA and clarified its involvement in the stabilization of mRNAs for synaptic vesicle proteins.
2020-04-10 | GSE131103 | GEO
Project description:In this study, we present the comparative transcriptome analysis of human osteoblasts and their corresponding EVs using next-generation sequencing. We demonstrate that osteoblast-EVs are specifically depleted of cellular mRNAs that encode proteins involved in basic cellular activities, such as cytoskeletal functions, cell survival and apoptosis. In contrast, EVs are significantly enriched with 254 mRNAs that are associated with protein translation and RNA processing. Moreover, mRNAs enriched in EVs encode proteins important for communication with the surrounding cells, in particular with osteoclasts, adipocytes and hematopoietic stem cells. Strikingly, EVs are particularly enriched with RAB13 mRNA, which is linked to vesicular trafficking. The latter suggests that EVs may affect vesicle production in target cells. These findings provide the foundation for understanding the molecular mechanism and function of EV-mediated interactions between osteoblasts and the surrounding bone microenvironment.
2017-06-26 | GSE85761 | GEO