Plasma Exosomes in Insulin Resistant Obesity Exacerbate Progression of Triple Negative Breast Cancer
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PROVIDER: PRJNA1188106 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancer, the most common cancer among women worldwide, continues to pose significant public health challenges. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat due to the absence of receptors for estrogen, progesterone, or human epidermal growth factor receptor 2, rendering TNBC refractory to conventional targeted therapies. Emerging research underscores the exacerbating role of metabolic disorders, such as type 2 diabetes and obesity, on TNBC aggressiveness. Here, we investigate the critical cellular and molecular factors underlying this link. We explore the pivotal role of circulating plasma exosomes in modulating the tumor microenvironment and enhancing TNBC aggressiveness. We find that plasma exosomes from diet-induced obesity mice induce epithelial-mesenchymal transition features in TNBC cells, leading to increased migration in vitro and enhanced metastasis in vivo. We build on our previous reports demonstrating that plasma exosomes from obese, diabetic patients, and exosomes from insulin-resistant 3T3-L1 adipocytes, upregulate key transcriptional signatures of epithelial-mesenchymal transition in breast cancer. Bioinformatic analysis reveals that TNBC cells exhibit higher expression and activation of proteins related to the Rho-GTPase cascade, particularly the small Ras-related protein Rac1. Our approach suggests novel therapeutic targets and exosomal biomarkers, ultimately to improve prognosis for TNBC patients with co-morbid metabolic disorders.
2025-07-14 | PXD057911 | Pride
Project description:This dataset includes mRNA sequencing data obtained from cells treated with plasma-derived exosomes from mice fed high-fat (HFD) or low-fat (LFD) diets. RNA was extracted and sequenced to investigate differential gene expression and associated biological pathways. The aim of the study is to elucidate how metabolic dysregulation in obesity influences exosome-mediated gene expression changes, contributing to cancer aggressiveness. Data include raw and processed mRNA sequencing files from triplicates for each condition.
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Project description:Background and Aims: Insulin resistance is a key factor in the pathogenesis of NAFLD. We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. Methods: Adipose tissue inflammation (macrophage and T cell content and gene expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed by a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in three groups stratified by adiposity, insulin sensitivity and intrahepatic triglyceride (IHTG) content: 1) metabolically-healthy lean (LEAN; n=14); 2) metabolically-healthy obese with normal IHTG content (OB-NL; n=28); and 3) metabolically-unhealthy obese with NAFLD (OB-NAFLD; n=28). The effect of plasma and SAAT-derived exosomes on insulin action (insulin-stimulated Akt phosphorylation) in human skeletal muscle myotubes was assessed in a subset of participants. Results: Proinflammatory macrophages, proinflammatory CD4 and CD8 T cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve (AUC) were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration AUC were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes obtained from the OB-NAFLD group impaired insulin action in myotubes. Conclusion: These results suggest SAAT-derived exosomes and PAI-1 are involved in the pathogenesis of systemic insulin resistance in people with obesity and NAFLD. ClinicalTrials.gov number: NCT02706262.
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Project description:Exosomes which are nano-vesicles and released from living cells, have attracted more attention as an important mediator for cell-to-cell communication. Given that obesity often causes insulin resistance, it is significant to test whether exosomes derived from obesity adipose tissue possess any capacity in regulating insulin sensitivity. In this study we purified exosomes from the adipose tissue. Exosomes derived from ob/ob mice (Ob-exosomes) and B6 mice fed a high-fat diet (HFD-exosomes) displayed similar size and molecular maker to those originated from the normal B6 mice (WT-exosomes), but their regulatory role in insulin sensitivity was opposite. Abundant exosomal miRNAs were detected by the Next Generation Sequencing. Ob-exosomes encapsulated the lower levels of miR-141-3p compared to WT-exosomes, furthermore, miR-141-3p can be effectively delivered into AML12 cells accompanied by the absorption of Ob-exosomes and WT-exosomes. But the absorption of miR-141-3p from adipose tissues to AML12 cells could be blocked by GW4869, an inhibitor of exosome biogenesis and release. Importantly, the exosomal miR-141-3p functionally down-regulated its target gene Pten expression in AML12 cells, and the knockdown of miR-141-3p inhibited the insulin response and glucose uptake in AML12 cells, however Ob-exosomes-mediated inhibitory effects on insulin function disappeared after overexpression of miR-141-3p. These data indicate that the absorption of exosomes released from obesity adipose tissue including lower level of miR-141-3p than healthy adipose tissue into hepatocytes can significantly inhibit the insulin sensitivity and glucose uptake. Thus, our study may certify a novel mechanism that the secretion of “harmful” exosomes from obesity adipose tissues cause insulin resistance.
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Project description:The objective of this study was to investigate whether placental exosomes in gestational diabetes mellitus (GDM) carries a specific set of miRNAs associated with skeletal muscle insulin sensitivity. Exosomes were isolated from chorionic villi-conditioned media and plasma from normal and GDM pregnancies. A specific set of miRNAs was identified to be selectively enriched within exosomes when compared to their cells of origin indicating specific packaging of miRNAs into exosomes. In addition, miRNA expression varies in a consistent pattern in placenta, placental-derived exosomes, circulating exosomes and skeletal muscle in GDM.
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Project description:Prospective epidemiological studies have consistently supported that pancreatic cancer associated new-onset diabetes mellitus (PC-DM) is probably an important clue for early diagnosis of pancreatic cancer (PC). However, the mechanism underlying remains fragmentary. In this study, two types of exosomes released by murine pancreatic cancer cells and murine pancreatic ductal epithelial cells were isolated，and their effects on skeletal muscle cells were invested. The results showed that PC-derived exosomes can readily enter C2C12 myotubes, and then induce lipidosis, glucose intake inhibition. We also found that PC-derived exosomes can inhibit Insulin and PI3K/Akt signaling, in which insulin-induced FoxO1 nuclear exclusion is preserved while Glut4 trafficking is impaired. In addition, further microarray and Kyoto encyclopedia of genes and genomes (KEGG) analysis prompted that exosomal microRNAs (miRNAs) probably play an critical role in this process, which also has been preliminarily demonstrated in vitro. Taking together, these results suggest that PC-derived exosomes induce insulin resistance (IR) of skeletal muscle cells through Insulin and PI3K/Akt/FoxO1 signaling pathway, and exosomal miRNAs are probably involved. The novel findings also support the theories of cancer “metabolic reprogramming” and “metabolic crosstalk”.
2017-08-11 | GSE95741 | GEO
Project description:Exosomes are cell-released bioactive nanovesicles now considered as new partners in the inter-organ cross-talks. The possibility that skeletal muscle (SkM)-derived exosomes act as a mode of systemic communication has hitherto never been described. Thus, in this study we have tested the hypothesis that through the exosomal route, muscle cells might transmit specific signals during insulin-resistance.
2016-11-03 | GSE52048 | GEO
Project description:This dataset includes mRNA sequencing data obtained from 4T1 cells, either from in vitro cell culture, or clonogenic assay from brain, or primary tumor treated with exosomes from insulin sensitive (IS) or induslin resistant (IR) adipocytes; and 4T1 cells cultured in vitro and treated with miR-145a-3p. Exosomal small RNA from IS and IR aidpocytes derived exsomes were also included. RNA was extracted and sequenced to investigate differential gene expression and associated biological pathways. The aim of the study is to elucidate how insulin resistance in adipocytes influences gene expression, cancer aggressiveness and metastasis. Data include raw and processed mRNA sequencing files from replicates for each condition.
2025-06-16 | GSE286275 | GEO
Project description:Cellular CYP2E1 is well-known to mediate alcohol- (ALC) and acetaminophen- (APAP) induced toxicity in hepatic and extra-hepatic cells. Although exosomes have been gaining importance in understanding mechanism of intra- and inter-cellular communication, the functional role of drug metabolizing cytochrome P450 (CYP) enzymes in human plasma exosomes are yet to be explored. In our previous study, we reported that human plasma-derived exosomes contain substantial level of functional CYP2E1. In the current project, we investigated the potential role of plasma exosomal CYP2E1 in mediating ALC- and APAP-induced toxicity. We treated hepatic and extra-hepatic (monocytic) cells with exosomes ± ALC/APAP. We observed that the plasma exosomes containing CYP2E1 cargo further exacerbate ALC- and APAP-induced toxicity in both hepatic and monocytic cells. Further, both exosomes- and ALC/APAP-induced toxicity was reduced/abolished by a selective inhibitor of CYP2E1 enzyme activity (diallyl ether). However, only ALC-, but not exosome-induced toxicity was reduced/abolished by CYP2E1 siRNA. These findings suggest that ALC/APAP-induced toxicity in the presence of exosomes are mediated, at least in part, by CYP2E1 enzyme. To validate these in vitro findings, we characterized plasma exosomal contents in a binge-drinking animal model and their effect on ALC/APAP-induced toxicity in monocytic cells. Our results showed that ALC exposure caused a significant induction of the plasma exosomal CYP2E1 level in a binge drinking murine model. These exosomes containing increased levels of CYP2E1 caused significant toxicity in monocytic cells compared to exosomes derived from control mice. Overall, our results showed an important role of exosomal CYP2E1 in exacerbating ALC- and APAP-induced toxicity. The study is significant in terms of understanding the role of exosomal CYP2E1 in cell-cell interactions, and their effects on drug-induced toxicity.
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Project description:The foam cell-derived exosomes exacerbate ischemic white matter injury via transmitting metabolic defects to microglia
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