Extracellular vesicles secreted by highly metastatic clonal variants of osteosarcoma preferentially localize to the lungs and induce metastatic behaviour in poorly metastatic clones.
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.
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Rebecca
R
Macklin
Therapeutics Research Centre, School of Medicine, University of Queensland, Brisbane, Australia.
Haolu
H
Wang
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Dorothy
D
Loo
Queensland Brain Institute, The University of Queensland, Brisbane, Australia.|Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.
Sally
S
Martin
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Andrew
A
Cumming
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Na
N
Cai
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.|Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia.
Rebecca
R
Lane
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Natalia Saenz
NS
Ponce
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Eleni
E
Topkas
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Kerry
K
Inder
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Nicholas A
NA
Saunders
The University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Australia.
Liliana
L
Endo-Munoz
D001859:Bone Neoplasms / Q000473:pathology*; D002450:Cell Communication; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D000067128:Extracellular Vesicles / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology* / Q000556:secondary; D008854:Microscopy, Electron; D036641:Microscopy, Fluorescence, Multiphoton; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000000981:diagnostic imaging / Q000473:pathology* / Q000556:secondary; D040901:Proteomics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction
D043562:Receptors, G-Protein-Coupled
extracellular vesicles; interclonal communication; metastasis; osteosarcoma; pre-metastatic niche