Progression of Osteosarcoma from a Non-Metastatic to a Metastatic Phenotype Is Causally Associated with Activation of an Autocrine and Paracrine uPA Axis

PloS One
Liliana Endo-MunozNicholas A Saunders

Abstract

Pulmonary metastasis is the major untreatable complication of osteosarcoma (OS) resulting in 10-20% long-term survival. The factors and pathways regulating these processes remain unclear, yet their identification is crucial in order to find new therapeutic targets. In this study we used a multi-omics approach to identify molecules in metastatic and non-metastatic OS cells that may contribute to OS metastasis, followed by validation in vitro and in vivo. We found elevated levels of the urokinase plasminogen activator (uPA) and of the uPA receptor (uPAR) exclusively in metastatic OS cells. uPA was secreted in soluble form and as part of the protein cargo of OS-secreted extracellular vesicles, including exosomes. In addition, in the tumour microenvironment, uPA was expressed and secreted by bone marrow cells (BMC), and OS- and BMC-derived uPA significantly and specifically stimulated migration of metastatic OS cells via uPA-dependent signaling pathways. Silencing of uPAR in metastatic OS cells abrogated the migratory response to uPA in vitro and decreased metastasis in vivo. Finally, a novel small-molecule inhibitor of uPA significantly (P = 0.0004) inhibited metastasis in an orthotopic mouse model of OS. Thus, we show for the fir...Continue Reading

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Citations

Dec 18, 2018·Journal of Veterinary Internal Medicine·Andrew C PoonAnthony J Mutsaers
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Oct 30, 2020·International Journal of Nanomedicine·Victor C Kok, Cheng-Chia Yu
Nov 28, 2021·International Journal of Molecular Sciences·Viviana De MartinoAndrea Del Fattore

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Methods Mentioned

BETA
biopsies
FCS
PCR
Chip
antibody
Antibody Array
Assay
biopsy

Software Mentioned

ImmunoRatio
Bioconductor
Fusion
BLOCK
Limma
Lumi
iT
BeadStudio
Nikon NIS - Elements
SL

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