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New proteomic signature in circulating extracellular vesicles from tumor-draining and peripheral veins of patients with lung adenocarcinoma

ABSTRACT: The identification of noninvasive prognostic biomarkers for monitoring relapse in patients with locally advanced lung cancer remains a primary objective. Tumor-draining vein (TDV) plasma samples are known to be enriched in cancer biomarkers compared to peripheral vein (PV) samples. Therefore, we aimed to investigate the proteomic profile of extracellular vesicles (EVs) from TDV and PV plasma samples in patients undergoing surgery for lung adenocarcinoma. A comparison with proteomic analyzes from tumor and non-tumor tissues was performed in parallel. Purified EVs from TDV and PV plasma samples were characterized for size distribution and concentration using nanoparticles tracking analysis. Proteomic profiling of TDV-derived and PV-derived EVs was performed using mass spectrometry (nanoLC-MS/MS) analysis, as the proteomic profile of tumor tissue and adjacent non-tumoral counterparts. Twenty patients operated for a lung adenocarcinoma were enrolled.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Blood Plasma

DISEASE(S): Lung Cancer

SUBMITTER: Luc Negroni

LAB HEAD: Fabrice Lalloué

PROVIDER: PXD066683 | Pride | 2025-07-29

REPOSITORIES: Pride

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Project description:Background: The cancer-related mortality of primary liver cancer ranks third globally, and hepatocellular carcinoma (HCC) is predominant, posing a serious threat to patients' health. Understanding HCC's pathogenesis and target molecules is crucial for early diagnosis and prognosis. Extracellular vesicles (EVs) and their carried miRNAs impact tumor progression. This study aims to investigate miR-183-5p in HCC cell-derived EVs on angiogenesis, progression, and metastasis, and provide diagnostic and therapeutic evidence. Methods: q-PCR was used to evaluate the expression of miR-183-5p in HCC tissue and plasma EV samples. Contrast-enhanced ultrasound and The Cancer Genome Atlas evaluated its correlation with angiogenesis and prognosis. In vitro, cell counting kit-8 (CCK-8), colony formation, transwell, tube formation, and permeability assays examined the effect of HCC cell-derived EVs on human umbilical vein endothelial cells (HUVECs). Subcutaneous tumor and lung metastasis models in nude mice verified it in vivo effects. RNA sequencing and databases predicted downstream genes and pathways, and dual luciferase and western blotting assays verified binding and activation. Conditioned medium from treated HUVECs was used on HCC cells, and chemokine levels measured. The CCL20/CCR6 axis effect was studied in vitro and in vivo by knocking down CCR6. Results: This study revealed the abnormal upregulation of miR-183-5p in both tissues and plasma EVs from patients with HCC, and its association with unfavorable prognosis. In vivo experiments, the promoting effects of miR-183-5p in HCC cell-derived EVs on the progression, metastasis and angiogenesis were verified by employing subcutaneous tumor formation models and lung metastasis models in nude mice. We demonstrated that miR-183-5p in HCC cell-derived EVs induced HUVECs proliferation, migration, angiogenesis and permeability by downregulating SIK1 expression and activating the PI3K/AKT signaling pathway in vitro. Moreover, stimulated HUVECs could secrete the chemokine CCL20 and induce HCC progression and metastasis through the CCL20/CCR6 signal pathway in vitro and in vivo. Conclusion: The findings indicated that miR-183-5p delivered by EVs from HCC cells is crucial in mediating the communication between HUVECs and HCC cells by modulating the SIK1/PI3K/AKT and CCL20/CCR6 signaling pathways, and EVs-miR-183-5p might be a potential therapeutic target for HCC patients.

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.

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New proteomic signature in circulating extracellular vesicles from tumor-draining and peripheral veins of patients with lung adenocarcinoma

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