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Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

ABSTRACT: Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to investigate MM-derived exosomes from distinct human models and identify select cargo protein networks associated with angiogenesis, metastasis, and immunoregulation. Utilising bioinformatics pathway/network analyses, and correlation with previous studies on tumour exosomes, we defined a select mesothelioma exosomal signature (mEXOS, 570 proteins) enriched in tumour antigens and various cancer-specific signalling (HPGD/ENO1/OSMR) and secreted modulators (FN1/ITLN1/MAMDC2/PDGFD/GBP1). Notably, such circulating cargo offers unique insights into mesothelioma progression and tumour microenvironment reprogramming. Functionally, we demonstrate that oncogenic exosomes facilitate the migratory capacity of fibroblast/endothelial cells, supporting the systematic model of MM progression associated with vascular remodelling and angiogenesis. We provide biophysical and proteomic characterisation of exosomes, define a unique oncogenic signature (mEXOS), and demonstrate the regulatory capacity of exosomes in cell migration/tube formation assays. These findings contribute to understanding tumour-stromal crosstalk in the context of MM, and potential new diagnostic and therapeutic extracellular targets.

SUBMITTER: Greening DW

PROVIDER: S-EPMC5015102 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

Greening David W DW Ji Hong H Chen Maoshan M Robinson Bruce W S BW Dick Ian M IM Creaney Jenette J Simpson Richard J RJ

Scientific reports 20160908

Malignant mesothelioma (MM) is a highly-aggressive heterogeneous malignancy, typically diagnosed at advanced stage. An important area of mesothelioma biology and progression is understanding intercellular communication and the contribution of the secretome. Exosomes are secreted extracellular vesicles shown to shuttle cellular cargo and direct intercellular communication in the tumour microenvironment, facilitate immunoregulation and metastasis. In this study, quantitative proteomics was used to ...[more]

PMID: 27605433

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Project description:Introduction: Dysregulated genes play a critical role in the development and progression of cancer, suggesting their potential as novel independent biomarkers for cancer diagnosis and prognosis. Prognostic model-based gene expression profiles are not widely utilized in clinical medicine. We investigated the prognostic significance of an expression profile-based gene signature for outcome prediction in patients with malignant pleural mesothelioma (MPM). Methods: The gene expression profiles of a large cohort of patients with MPM were obtained and analyzed by repurposing publicly available microarray data. A gene-based risk score model was developed with the training dataset and then validated with the TCGA-MESO (mesothelioma) dataset. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the prognostic performance of survival prediction. The biological function of the prognostic genes was predicted using bioinformatics analysis. Results: Three genes in the training dataset (GSE2549) were identified as significantly associated with the overall survival (OS) of patients with MPM and were combined to develop a three-gene prognostic signature to stratify patients into low-risk and high-risk groups. The MPM patients of the training dataset in the low-risk group exhibited longer OS than those in the high-risk group (HR = 0.25, 95% CI = 0.11-0.56, P < 0.001). Similar prognostic values for the three-gene signature were observed in the validated TCGA-MESO cohort (HR = 0.53 95% CI = 0.33-0.85, P = 0.008). ROC analysis also demonstrated the good performance in predicting 3-year OS in the GEO and TCGA cohorts (KM-AUC for GEO = 0.989, KM-AUC for TCGA = 0.618). The C-statistic for the 3-gene model was 0.761. Validation with TCGA-MESO confirmed the model's ability to discriminate between risk groups in an alternative data set with fair performance (C-statistic: 0.68). Functional enrichment analysis suggested that these three genes may be involved in genetic and epigenetic events with known links to MPM. Conclusions: This study has identified and validated a novel 3-gene model to reliably discriminate patients at high and low risk of death in unselected populations of patients with MPM. Further larger, prospective multi-institutional cohort studies are necessary to validate this model.

Dataset Information

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

Publications

Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.

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