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Oncotarget. 2017 Jul 25;8(44):76241-76256. doi: 10.18632/oncotarget.19532. eCollection 2017 Sep 29.

Integration of genomic, transcriptomic and functional profiles of aggressive osteosarcomas across multiple species.

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Knight Cancer Institute, Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health and Sciences University, Portland, Oregon, USA.
Department of Pediatrics, Oregon Health and Sciences University, Portland, Oregon, USA.
Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Sciences University, Portland, Oregon, USA.
Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA.
Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado, USA.
Department of Pathology, Oregon Health and Sciences University, Portland, Oregon, USA.


In complex, highly unstable genomes such as in osteosarcoma, targeting aberrant checkpoint processes (metabolic, cell cycle or immune) may prove more successful than targeting specific kinase or growth factor signaling pathways. Here, we establish a comparative oncology approach characterizing the most lethal osteosarcomas identified in a biorepository of tumors from three different species: human, mouse and canine. We describe the development of a genetically-engineered mouse model of osteosarcoma, establishment of primary cell cultures from fatal human tumors, and a biorepository of osteosarcoma surgical specimens from pet dogs. We analyzed the DNA mutations, differential RNA expression and in vitro drug sensitivity from two phenotypically-distinct cohorts: tumors with a highly aggressive biology resulting in death from rapidly progressive, refractory metastatic disease, and tumors with a non-aggressive, curable phenotype. We identified ARK5 (AMPK-Related Protein Kinase 5, also referred to as NUAK Family Kinase 1) as a novel metabolic target present in all species, and independent analyses confirmed glucose metabolism as the most significantly aberrant cellular signaling pathway in a model system for highly metastatic tumors. Pathway integration analysis identified Polo Like Kinase 1 (PLK1)-mediated checkpoint adaptation as critical to the survival of a distinctly aggressive osteosarcoma. The tumor-associated macrophage cytokine CCL18 (C-C Motif Chemokine Ligand 18) was significantly over-expressed in aggressive human osteosarcomas, and a clustering of mutations in the BAGE (B Melanoma Antigen) tumor antigen gene family was found. The theme of these features of high risk osteosarcoma is checkpoint adaptations, which may prove both prognostic and targetable.


checkpoint adaptation; comparative oncology; metastases; osteosarcoma; osterix

Conflict of interest statement

CONFLICTS OF INTEREST C.K. has received single-time honoraria for scientific presentations at Novartis, Millennium/Takeda and GlaxoSmithKline, has research collaborations with Novartis, has sponsored research with Eli Lilly, has been a consultant to the NCI/CTEP Pediatric Preclinical Testing Program (PPTP), and is co-founder of First Ascent Biomedical.

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