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Transcriptome changes due to nuclear penetration of cancer extracellular vesicles

ABSTRACT: Extracellular membrane vesicles (EVs) function as vehicles of intercellular communication in autocrine or paracrine manner. We report that cancer-derived EV biomaterials reach nuclei of human melanoma and breast carcinoma cells and multipotent mesenchymal stromal cells (MSCs) through Rab7+ late endosome subdomains that penetrate into nuclear envelope invaginations. MSCs were exposed to cancer Evs in the presence or absence of drugs that block nucler import or export through the nuclear pores. Depletion of CD9 or inhibition of importin β1, two EV-associated molecules, abrogated the nuclear localization of EV-derived biomaterials and EV-induced early changes in MSC transcriptome notably in genes involved in inflammation. Also inhibition of nuclear export by leptomycin B inhibited early changes in MSC transcriptome. This novel cellular pathway may become a cancer therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83559 | GEO | 2016/10/01

SECONDARY ACCESSION(S): PRJNA326339

REPOSITORIES: GEO

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Project description:Background: Extracellular vesicles (EVs) isolated from mesenchymal stem/stromal cells (MSCs) contribute to recovery of damaged tissue in animals models of human disease. We have previously shown that EVs isolated from porcine MSCs transport mRNA and miRNA capable of modulating several cellular pathways in recipient cells, yet their proteome remained to be profiled. Using a quantitative proteomic strategy, we sought to study the protein cargo of porcine MSC-derived EVs to identify candidate molecules for mediating their therapeutic effect. Methods: Autologous MSCs were collected from abdominal fat of 3 female domestic pigs, and MSC-derived EVs were subsequently isolated, cultured, and characterized by the expression of typical MSC and EV markers. LC-MS/MS proteomic analysis was performed and proteins classified using the Panther Classification System. Functional pathway analysis was performed with DAVID 6.7. Three candidate proteins were selected for validation and their expression in EVs and MSCs confirmed by Western blot. Results: Proteomics analysis identified 5,469 protein groups in MSCs and 4,937 in EVs. Average protein intensity was higher in MSCs compared to EVs (p<0.0001). Differential expression analysis revealed 128 proteins upregulated in EVs vs. MSCs (log2 fold change>10, p<0.05), whereas 563 proteins were excluded from EVs (log2 fold change<-10, p<0.05). Biological functional analysis of proteins enriched in EVs indicated a broad distribution, with the most frequently represented categories being proteins involved in angiogenesis, blood coagulation, apoptosis, extracellular matrix remodeling, and regulation of inflammatory responses. Proteins excluded from EVs were mostly nuclear proteins and proteins involved in nucleotide binding and RNA splicing. Conclusions: The present study provides novel proteomic characterization of the biological signatures of porcine adipose MSC-derived EVs. The selective cargo that EVs shuttle may define the spectrum of their roles in mediating MSC intercellular communication.

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Transcriptome changes due to nuclear penetration of cancer extracellular vesicles

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