Inhibition of osteosarcoma metastasis in vivo by targeted downregulation of MMP1 and MMP9

•The 5-year survival rate of patients with metastatic osteosarcoma (OS) is extremely poor. Treatment strategies and survival rates for OS have remained constant for decades with no inclusion of biological therapies.•OS tumors are heterogeneous at the epigenetic, genomic, transcriptomic, proteomic and metabolomic levels as reflected in the histological and clinical progression. Consistent with this heterogeneity of OS tumors in patients, different human OS cell lines exhibit distinct expression patterns of matrix metalloproteinases (MMPs).•Here we show that MMP9 plays an important role in the formation of OS lung metastasis. Specifically, downregulation of MMP9, significantly blunted OS metastasis in vitro and in vivo.•This important finding that specific MMPs markedly contribute to the formation of lung metastasis, can constitute a stepping stone towards plausible personalized targeted treatment of OS. Osteosarcoma (OS) mortality stems from lung metastases. Matrix metalloproteinases (MMPs) facilitate metastatic dissemination by degrading extracellular matrix components. Herein we studied the impact of targeted MMP downregulation on OS metastasis. Differential gene expression analysis of human OS cell lines revealed high MMP9 expression in the majority of OS cell lines. Furthermore, 143B, a metastatic OS cell line, exhibited increased MMP1 and MMP9 mRNA levels. Gene set enrichment analysis on metastatic and non-metastatic OS patient specimens indicated epithelial-mesenchymal transition as the most enriched gene set, with MMP9 displaying strong association to genes in this network. Using the same dataset, Kaplan-Meier analysis revealed a correlation between MMP1 expression and dismal patient survival. Hence, we undertook targeted suppression of MMP1 and MMP9 gene expression in OS cell lines. The ability of OS cells to migrate and form colonies was markedly reduced upon MMP1 and MMP9 downregulation, whereas their cell proliferation capacity remained intact. MMP9 downregulation decreased tumor growth and lung metastases area in an orthotopic mouse OS model. Consistently, human OS lung metastasis specimens displayed marked MMP9 protein expression. Our findings highlight the role of MMP1 and MMP9 in OS metastasis, warranting further exploration of simultaneous inhibition of MMPs for future OS therapeutics. [Display omitted]