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Elucidating the transcriptional program of feline injection-site sarcoma using a cross-species mRNA-sequencing approach
- Source :
- BMC Cancer, BMC Cancer, Vol 19, Iss 1, Pp 1-18 (2019)
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- 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. Electronic supplementary material The online version of this article (10.1186/s12885-019-5501-z) contains supplementary material, which is available to authorized users.
- Subjects :
- Male
0301 basic medicine
Cancer Research
DNA Copy Number Variations
Primary Cell Culture
mRNA-seq
Antineoplastic Agents
Biology
Cat Diseases
SCNA
lcsh:RC254-282
Feline
Transcriptome
03 medical and health sciences
Dogs
0302 clinical medicine
Species Specificity
Cell Line, Tumor
Gene expression
Tumor Cells, Cultured
Genetics
medicine
Animals
Humans
Genes, Tumor Suppressor
RNA, Messenger
Gene
Comparative oncology
Sequence Analysis, RNA
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Cancer
Sarcoma
Oncogenes
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
Injection Site Reaction
3. Good health
Gene expression profiling
030104 developmental biology
MRNA Sequencing
Oncology
030220 oncology & carcinogenesis
Cats
Cancer research
Research Article
Subjects
Details
- ISSN :
- 14712407
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- BMC Cancer
- Accession number :
- edsair.doi.dedup.....03d6b882a567f75daa1c96a0f415bf7f