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

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.

SUBMITTER: Davis LE

PROVIDER: S-EPMC5652702 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Davis Lara E LE Jeng Sophia S Svalina Matthew N MN Huang Elaine E Pittsenbarger Janét J Cantor Emma L EL Berlow Noah N Seguin Bernard B Mansoor Atiya A McWeeney Shannon K SK Keller Charles C

Oncotarget 20170725 44

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 osteosarc ...[more]

PMID: 29100308

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Project description:BACKGROUND:Salinity is a major abiotic stress that limits upland cotton growth and reduces fibre production worldwide. To reveal genetic regulation via transcript and protein levels after salt stress, we comprehensively analysed the global changes in mRNA, miRNA, and protein profiles in response to salt stress in two contrasting salt-tolerant cotton genotypes. RESULTS:In the current study, proteomic and mRNA-seq data were combined to reveal that some genes are differentially expressed at both the proteomic and mRNA levels. However, we observed no significant change in mRNA corresponding to most of the strongly differentially abundant proteins. This finding may have resulted from global changes in alternative splicing events and miRNA levels under salt stress conditions. Evidence was provided indicating that several salt stress-responsive proteins can alter miRNAs and modulate alternative splicing events in upland cotton. The results of the stringent screening of the mRNA-seq and proteomic data between the salt-tolerant and salt-sensitive genotypes identified 63 and 85 candidate genes/proteins related to salt tolerance after 4 and 24 h of salt stress, respectively, between the tolerant and sensitive genotype. Finally, we predicted an interaction network comprising 158 genes/proteins and then discovered that two main clusters in the network were composed of ATP synthase (CotAD_74681) and cytochrome oxidase (CotAD_46197) in mitochondria. The results revealed that mitochondria, as important organelles involved in energy metabolism, play an essential role in the synthesis of resistance proteins during the process of salt exposure. CONCLUSION:We provided a plausible schematic for the systematic salt tolerance model; this schematic reveals multiple levels of gene regulation in response to salt stress in cotton and provides a list of salt tolerance-related genes/proteins. The information here will facilitate candidate gene discovery and molecular marker development for salt tolerance breeding in cotton.

Dataset Information

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

Publications

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

Similar Datasets

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