Dataset Information

TGF-β signaling activation modulates the biology of tumor-derived extracellular cellular vesicles

ABSTRACT: Tumor-derived extracellular vesicles (EVs) have been associated with cancer progression and metastasis due to the transfer of bioactive molecules in between the tumor microenvironment. Although Transforming Growth Factor-β (TGF-β) signaling associated molecules have been implicated as cargo of EVs, the role of TGF-β pathway on EV’s biology to promote tumorigenesis is poorly understood. Hence, we aimed to describe the impact of TGF-β signaling on biogenesis and functional transfer of cargo from tumor-derived EVs induced by TGF-β (EV+TGF-β1). To this end, EV-fractions enriched in CD81 or Cholerae toxin B chain (CTB) were isolated from the vesicular secretome fraction (VSF) of human breast cancer and lung adenocarcinoma cells and further characterized.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: José Eduardo Araújo

LAB HEAD: Janne Lehtiö

PROVIDER: PXD039591 | Pride | 2025-05-06

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20210826_EAAMDM1_18_3h_5uL_sample1.msf	Msf
	20210826_EAAMDM1_18_3h_5uL_sample1.raw	Raw
	20210826_EAAMDM1_18_3h_5uL_sample10.msf	Msf
	20210826_EAAMDM1_18_3h_5uL_sample10.raw	Raw
	20210826_EAAMDM1_18_3h_5uL_sample11.msf	Msf

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Publications

TGF-β induces cholesterol accumulation to regulate the secretion of tumor-derived extracellular vesicles.

Rodrigues-Junior Dorival Mendes DM Tsirigoti Chrysoula C Psatha Konstantina K Kletsas Dimitris D Aivaliotis Michalis M Heldin Carl-Henrik CH Moustakas Aristidis A

Journal of experimental & clinical cancer research : CR 20250206 1

<h4>Background</h4>Cancer cells are avid extracellular vesicle (EV) producers. EVs transport transforming growth factor-β (TGF-β), which is commonly activated under late stages of cancer progression. Nevertheless, whether TGF-β signaling coordinates EV biogenesis is a relevant topic that remains minimally explored.<h4>Method</h4>We sought after specific TGF-β pathway mediators that could regulate EV release. To this end, we used a large number of cancer cell models, coupled to EV cell biological ...[more]

PMID: 39910665

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Project description:Background: Acute coronary syndromes (ACS) are associated with aberrant gene expression and epigenetic mechanisms. In particular, de novo DNA methylation is typically linked to gene silencing, but its role in heart disease remains not fully understood. Extracellular vesicles (EVs) are active components in cellular communication for their ability to carry a plethora of signalling biomolecules, thus representing a promising new diagnostic/therapeutic approach in cardiovascular diseases (CVDs). Indeed, there is the need of novel biomarkers for ACS prediction and timely detection. Purpose: We hypothesized that specific epigenetic signals can be carried by EVs. In this regard, we isolated and characterized circulating EVs from ACS patients and evaluated their potential role to influence DNA methylation in target cells. Methods: Circulating EVs were recovered, by ultracentrifugation, from plasma samples of 19 ACS patients and 50 healthy subjects (HS). Nanoparticle tracking analysis (NTA) and western blot (WB) were used to confirm the EVs integrity and purity. Peripheral blood mononuclear cells (PBMCs) of volunteer donors were treated with both ACS and HS derived EVs and genomic DNA was extracted to perform epigenome wide analysis through Reduced Representation Bisulfite Sequencing. ShinyGO, PANTHER, and STRING tools were interrogated to perform GO and PPI network analyses. Flow Cytometry, qRT-PCR, and WB analysis were also performed to evaluate and validate both intra-vesicular and intra-cellular signals. Results: Plasma ACS-derived EVs showed a significant up-regulation of DNA methyltransferases (DNMTs) gene expression levels as compared to HS (P<0.001). Specifically, de novo methylation transcripts, as DNMT3A and DNMT3B were significantly increased in plasma ACS-EVs. DNA methylation analysis of PBMCs from volunteer donors treated with HS- and ACS-derived EVs showed that RNF166 and CCND3 genes resulted the most hyper- and hypo-methylated, respectively, after by ACS-EV treatment. In addition, PPI network analysis specifically evidenced the subnetwork with SRC, as a hub gene, connecting it to NOTCH1, FOXO3, CDC42, IKBKG, RXRA, DGKG, known as important genes already involved in the onset of CVDs. Surprising, other novel genes, BAIAP2, SYP, CHL1, and SHB, which were hypomethylated, were found significantly overexpressed in PBMCs (P<0.005), underlying the fundamental modulating properties of EV cargo in atherosclerosis. Conclusions: These findings support the significant role of ACS plasma-derived EVs, inducing de novo DNA methylation signals, and modulating specific signaling pathways in target cells.