Multiple Myeloma Derived Extracellular Vesicle Uptake by Monocyte Cells Stimulates IL-6 and MMP-9 Secretion and Promotes Cancer Cell Migration and Proliferation

Simple Summary Multiple myeloma is an incurable blood cancer that arises due to the uncontrolled growth of plasma cells in the bone marrow. The progression of multiple myeloma is dependent on communication between the plasma cells and other cells within the bone marrow, and extracellular vesicles (EVs) are implicated in the cell communication. The aim of this study was to investigate the role of EVs secreted by multiple myeloma cells on monocyte cells. We revealed that multiple myeloma cell-derived EVs are taken up by monocyte cells. EV uptake by monocytes led to increased secretion of pro-inflammatory factors, which in turn created an environment that enhanced myeloma cell migration and growth that is associated with cancer progression. Investigation into the EV contents revealed potential mechanisms by which multiple myeloma EVs promote cancer progression.Abstract Multiple Myeloma (MM) is an incurable haematological malignancy caused by uncontrolled growth of plasma cells. MM pathogenesis is attributed to crosstalk between plasma cells and the bone marrow microenvironment, where extracellular vesicles (EVs) play a role. In this study, EVs secreted from a panel of MM cell lines were isolated from conditioned media by ultracentrifugation and fluorescently stained EVs were co-cultured with THP-1 monocyte cells. MM EVs from three cell lines displayed a differential yet dose-dependent uptake by THP-1 cells, with H929 EVs displaying the greatest EV uptake compared to MM.1s and U266 EVs suggesting that uptake efficiency is dependent on the cell line of origin. Furthermore, MM EVs increased the secretion of MMP-9 and IL-6 from monocytes, with H929 EVs inducing the greatest effect, consistent with the greatest uptake efficiency. Moreover, monocyte-conditioned media collected following H929 EV uptake significantly increased the migration and proliferation of MM cells. Finally, EV proteome analysis revealed differential cargo enrichment that correlates with disease progression including a significant enrichment of spliceosome-related proteins in H929 EVs compared to the U266 and MM.1s EVs. Overall, this study demonstrates that MM-derived EVs modulate monocyte function to promote tumour growth and metastasis and reveals possible molecular mechanisms involved.