Dataset Information

Signaling networks transported by EVs drive phenocopying of migratory behavior between tumor cells

ABSTRACT: Tumors are heterogeneous with respect to mutational pattern, gene expression and microenvironment. This heterogeneity leads to large functional intratumoral differences in tumor cell behavior so that a tumor may contain or develop small fractions of cells that possess properties to migrate, metastasize or evade therapy treatment. In recent years, extracellular vesicles (EVs) have attracted a lot of attention as microenvironmental intercellular messenger that may severely complicate tumor heterogeneity. EVs are small lipid membrane-enclosed vesicles that carry biologically active molecules including lipids, proteins, DNA and various RNA species. Although accumulating evidence suggest that tumor cells can phenocopy behavior through exchange of EVs, it is widely debated how the transfer of small amounts of cargo can mediate this effect. We isolated EVs from tumors grown in mice and identified that sub tumor clones with distinct metastatic potential transfer networks of RNAs and proteins involved in migration, and leads to phenocopying of migratory behavior.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Melanocyte, Whole Body

SUBMITTER: Sander Piersma

LAB HEAD: Connie Ramona Jimenez

PROVIDER: PXD006439 | Pride | 2018-06-22

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	MaxQuant_Output.zip	Other
	QE2_160128_OPL4022_SCS_EVs_and_LYS_A1.raw	Raw
	QE2_160128_OPL4022_SCS_EVs_and_LYS_A2.raw	Raw
	QE2_160128_OPL4022_SCS_EVs_and_LYS_A3.raw	Raw
	QE2_160128_OPL4022_SCS_EVs_and_LYS_A4_160202090357.raw	Raw

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Publications

Cancer cells copy migratory behavior and exchange signaling networks via extracellular vesicles.

Steenbeek Sander C SC Pham Thang V TV de Ligt Joep J Zomer Anoek A Knol Jaco C JC Piersma Sander R SR Schelfhorst Tim T Huisjes Rick R Schiffelers Raymond M RM Cuppen Edwin E Jimenez Connie R CR van Rheenen Jacco J

The EMBO journal 20180614 15

Recent data showed that cancer cells from different tumor subtypes with distinct metastatic potential influence each other's metastatic behavior by exchanging biomolecules through extracellular vesicles (EVs). However, it is debated how small amounts of cargo can mediate this effect, especially in tumors where all cells are from one subtype, and only subtle molecular differences drive metastatic heterogeneity. To study this, we have characterized the content of EVs shed <i>in vivo</i> by two clo ...[more]

PMID: 29907695

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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.