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Secreted primary human malignant mesothelioma exosome signature reflects oncogenic cargo

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journal contribution
posted on 05.08.2021, 06:04 by David GreeningDavid Greening, H Ji, Maoshan Chen, BWS Robinson, IM Dick, J Creaney, Richard SimpsonRichard Simpson
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.

Funding

Authors are supported, in part, by the National Health and Medical Research Council of Australia program grant APP487922 (R.J.S.), National Health and Medical Research Council Centres of Research Excellence 628727 (R.J.S., B.W.S.R., J.C.). D.W.G. is supported by the LIMS Molecular Biology Stone Fellowship, La Trobe University Research Focus Area Leadership Grant, and La Trobe University Start-up Fund. M.C. is supported by a La Trobe University Postgraduate Scholarship. Proteomics in this study was supported using the Mass Spectrometry and Proteomics facility, La Trobe University.

History

Publication Date

08/09/2016

Journal

Scientific Reports

Volume

6

Issue

1

Article Number

32643

Pagination

18p.

Publisher

Springer Nature

ISSN

2045-2322

Rights Statement

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