Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo.
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.
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
David W
DW
Greening
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
Hong
H
Ji
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
Maoshan
M
Chen
National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, 6009, Australia.|Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Western Australia, 6009, Australia.
Bruce W S
BW
Robinson
National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, 6009, Australia.
Ian M
IM
Dick
National Centre for Asbestos Related Diseases, School of Medicine and Pharmacology, University of Western Australia, 6009, Australia.|Australian Mesothelioma Tissue Bank, Sir Charles Gairdner Hospital, Perth, Western Australia, 6009, Australia.
Jenette
J
Creaney
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
Richard J
RJ
Simpson
D002450:Cell Communication / Q000235:genetics; D045744:Cell Line, Tumor; D055354:Exosomes / Q000235:genetics* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009363:Neoplasm Proteins / Q000235:genetics*; D040901:Proteomics; D059016:Tumor Microenvironment / Q000235:genetics
D009363:Neoplasm Proteins