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

Lara E. Davis, Sophia Jeng, Matthew N. Svalina, Elaine Huang, Janét Pittsenbarger, Emma L. Cantor, Noah Berlow, Bernard Seguin, Atiya Mansoor, Shannon K. McWeeney, Charles Keller

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)76241-76256
Number of pages16
JournalOncotarget
Volume8
Issue number44
DOIs
StatePublished - 2017

Keywords

  • Checkpoint adaptation
  • Comparative oncology
  • Metastases
  • Osteosarcoma
  • Osterix

ASJC Scopus subject areas

  • Oncology

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    Davis, L. E., Jeng, S., Svalina, M. N., Huang, E., Pittsenbarger, J., Cantor, E. L., Berlow, N., Seguin, B., Mansoor, A., McWeeney, S. K., & Keller, C. (2017). Integration of genomic, transcriptomic and functional profiles of aggressive osteosarcomas across multiple species. Oncotarget, 8(44), 76241-76256. https://doi.org/10.18632/oncotarget.19532