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Elucidating the transcriptional program of feline injection-site sarcoma using a cross-species mRNA-sequencing approach.
Wei, Qi; Ramsey, Stephen A; Larson, Maureen K; Berlow, Noah E; Ochola, Donasian; Shiprack, Christopher; Kashyap, Amita; Séguin, Bernard; Keller, Charles; Löhr, Christiane V.
Afiliação
  • Wei Q; Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA.
  • Ramsey SA; Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA. stephen.ramsey@oregonstate.edu.
  • Larson MK; Department of Clinical Sciences, Oregon State University, Corvallis, OR, USA.
  • Berlow NE; Children's Cancer Therapy Development Institute, Beaverton, OR, USA.
  • Ochola D; Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA.
  • Shiprack C; Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA.
  • Kashyap A; Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA.
  • Séguin B; Flint Animal Cancer Center, Colorado State University, Fort Collins, CO, USA.
  • Keller C; Children's Cancer Therapy Development Institute, Beaverton, OR, USA.
  • Löhr CV; Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA. christiane.loehr@oregonstate.edu.
BMC Cancer ; 19(1): 311, 2019 Apr 04.
Article em En | MEDLINE | ID: mdl-30947707
BACKGROUND: Feline injection-site sarcoma (FISS), an aggressive iatrogenic subcutaneous malignancy, is challenging to manage clinically and little is known about the molecular basis of its pathogenesis. Tumor transcriptome profiling has proved valuable for gaining insights into the molecular basis of cancers and for identifying new therapeutic targets. Here, we report the first study of the FISS transcriptome and the first cross-species comparison of the FISS transcriptome with those of anatomically similar soft-tissue sarcomas in dogs and humans. METHODS: Using high-throughput short-read paired-end sequencing, we comparatively profiled FISS tumors vs. normal tissue samples as well as cultured FISS-derived cell lines vs. skin-derived fibroblasts. We analyzed the mRNA-seq data to compare cancer/normal gene expression level, identify biological processes and molecular pathways that are associated with the pathogenesis of FISS, and identify multimegabase genomic regions of potential somatic copy number alteration (SCNA) in FISS. We additionally conducted cross-species analyses to compare the transcriptome of FISS to those of soft-tissue sarcomas in dogs and humans, at the level of cancer/normal gene expression ratios. RESULTS: We found: (1) substantial differential expression biases in feline orthologs of human oncogenes and tumor suppressor genes suggesting conserved functions in FISS; (2) a genomic region with recurrent SCNA in human sarcomas that is syntenic to a feline genomic region of probable SCNA in FISS; and (3) significant overlap of the pattern of transcriptional alterations in FISS with the patterns of transcriptional alterations in soft-tissue sarcomas in humans and in dogs. We demonstrated that a protein, BarH-like homeobox 1 (BARX1), has increased expression in FISS cells at the protein level. We identified 11 drugs and four target proteins as potential new therapies for FISS, and validated that one of them (GSK-1059615) inhibits growth of FISS-derived cells in vitro. CONCLUSIONS: (1) Window-based analysis of mRNA-seq data can uncover SCNAs. (2) The transcriptome of FISS-derived cells is highly consistent with that of FISS tumors. (3) FISS is highly similar to soft-tissue sarcomas in dogs and humans, at the level of gene expression. This work underscores the potential utility of comparative oncology in improving understanding and treatment of FISS.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sarcoma / Doenças do Gato / Perfilação da Expressão Gênica / Reação no Local da Injeção Tipo de estudo: Etiology_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sarcoma / Doenças do Gato / Perfilação da Expressão Gênica / Reação no Local da Injeção Tipo de estudo: Etiology_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article