Canine models for characterization, diagnosis, and treatment of human cancers using comparative canine-human transcriptomics

National Center For Advancing Translational Sciences

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Abstract

Cancer is a multifaceted disease. Its study requires interrogation of biology at multiple levels and bioinformatic analysis to analyze, integrate and interpret complex data streams produced by experiments. In recent years, researchers have invariably moved toward multi-omics studies of cancer. Our work here follows this trend, its impetus being to determine if transcriptomic biomarkers, discovered by analyses of RNA-Seq data from canine cancers, appear as expressed proteins in the tissue and blood of canines and humans. Previously, we analyzed canine transcriptomic data using gene co-expression clustering and discovered 5 gene modules relevant to lung adenocarcinoma, melanoma, osteosarcoma, B cell lymphoma and T cell lymphoma. We determined that the activation pattern of these modules is unique to each cancer and established canine-human equivalence by showing that the module activation patterns were similar in humans with the same type of cancers. Therefore, new cancer targets or therapies derived from these canine module profiles stand a better chance of translating to humans. In total, our common canine-human gene space equals 372 genes. Recently, working in this common genomic space, we ran proteomics experiments on canine tissue and blood. We found that 262 of the 372 expressed transcripts coded for expressed tissue proteins and are, therefore, potential targets for therapy. We found that 45 of the 262 proteins expressed in tissues were also expressed in blood, representing potential biomarkers for blood-based cancer detection. Using gene annotations, we identified cancer-specific mechanisms allowing tissue proteins to access the blood compartment. This understanding can help future researchers focus their efforts on regions of the proteome enriched for blood diagnostic proteins. We have begun testing drug combinations against canine cancer cell lines. Those found to be active in vitro will be confirmed by testing in vivo in patient dogs. Large-scale proteomics studies in canine will be performed to gather statistics confirming biomarker specificity among cancer types. Biomarkers, drug combinations, and important genes that are found to be consistent across both human and canine cancers will inform the design of future clinical studies.