Extracellular vesicles secreted by highly metastatic clonal variants of osteosarcoma preferentially localize to the lungs and induce metastatic behaviour in poorly metastatic clones
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Rebecca Macklin1, Haolu Wang2, Dorothy Loo1, Sally Martin3,4, Andrew Cumming1, Na Cai1, Rebecca Lane1,4, Natalia Saenz Ponce1, Eleni Topkas1, Kerry Inder1, Nicholas A Saunders1, Liliana Endo-Munoz1
1The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia
2Therapeutics Research Centre, School of Medicine, University of Queensland, Brisbane, Australia
3Queensland Brain Institute, The University of Queensland, Brisbane, Australia
4Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia
Liliana Endo-Munoz, email: firstname.lastname@example.org
Keywords: osteosarcoma, metastasis, extracellular vesicles, interclonal communication, pre-metastatic niche
Received: November 16, 2015 Accepted: May 25, 2016 Published: June 02, 2016
Osteosarcoma (OS) is the most common pediatric bone tumor and is associated with the emergence of pulmonary metastasis. Unfortunately, the mechanistic basis for metastasis remains unclear. Tumor-derived extracellular vesicles (EVs) have been shown to play critical roles in cell-to-cell communication and metastatic progression in other cancers, but their role in OS has not been explored. We show that EVs secreted by cells derived from a highly metastatic clonal variant of the KHOS cell line can be internalized by a poorly metastatic clonal variant of the same cell line and induce a migratory and invasive phenotype. This horizontal phenotypic transfer is unidirectional and provides evidence that metastatic potential may arise via interclonal co-operation. Proteomic analysis of the EVs secreted by highly metastatic OS clonal variants results in the identification of a number of proteins and G-protein coupled receptor signaling events as potential drivers of OS metastasis and novel therapeutic targets. Finally, multiphoton microscopy with fluorescence lifetime imaging in vivo, demonstrated a preferential seeding of lung tissue by EVs derived from highly metastatic OS clonal variants. Thus, we show that EVs derived from highly metastatic clonal variants of OS may drive metastatic behaviour via interclonal co-operation and preferential colonization of the lungs.
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