"This is the peer reviewed version of the
following article: Reale, A., Carmichael, I., Xu, R., et al. (2021). Human myeloma cell- and plasma-derived extracellular vesicles
contribute to functional regulation of stromal cells. Proteomics, 21, e2000119. https://doi.org/10.1002/pmic.202000119
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Circulating small extracellular vesicles (sEV) represent promising non-invasive biomarkers that may aid in the diagnosis and risk-stratification of multiple myeloma (MM), an incurable blood cancer. Here, we comprehensively isolated and characterized sEV from human MM cell lines (HMCL) and patient-derived plasma (psEV) by specific EV-marker enrichment and morphology. Importantly, we demonstrate that HMCL-sEV are readily internalised by stromal cells to functionally modulate proliferation. psEV were isolated using various commercial approaches and pre-analytical conditions (collection tube types, storage conditions) assessed for sEV yield and marker enrichment. Functionally, MM-psEV were shown to regulate stromal cell proliferation and migration. In turn, pre-educated stromal cells favour HMCL adhesion. psEV isolated from patients with both pre-malignant plasma cell disorders (monoclonal gammopathy of undetermined significance [MGUS]; smouldering MM [SMM]) and MM have a similar ability to promote cell migration and adhesion, suggesting a role for both malignant and pre-malignant sEV in disease progression. Proteomic profiling of MM-psEV (305 proteins) revealed enrichment of oncogenic factors implicated in cell migration and adhesion, in comparison to non-disease psEV. This study describes a protocol to generate morphologically-intact and biologically functional sEV capable of mediating the regulation of stromal cells, and a model for the characterization of tumour-stromal cross-talk by sEV in MM. This article is protected by copyright. All rights reserved.
National Health and Medical Research Council. Grant Numbers: 1057741 (DWG), 1139489 (DWG) Faculty of Medicine, Nursing and Health Sciences, Monash University Helen Amelia Hains Fellowship (DWG) Department of Education, Skills and Employment, Australian Government (AR)
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