Elucidating the transcriptional program of feline injection-site sarcoma using a cross-species mRNA-sequencing approach

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.

Free Fatty Acid Receptors 2 and 3 as Microbial Metabolite Sensors to Shape Host Health: Pharmacophysiological View

“…FFAR3 gene expression was found in the colon, cecum, thymus, spleen, pancreas, adipose tissue, lungs, duodenum, jejunum, and ileum of the New Zealand rabbit [90]. FFAR3 gene was reported to be absent in chicken genome [91]. FFAR3 was also found to express in adipose tissues of goats [111] and sheep [112].…”

“…In New Zealand rabbits FFAR2 expresses in thymus, spleen, pancreas, adipose tissue, lungs, duodenum, jejunum, cecum ileum and colon [90]. In chickens, FFAR2 paralog genes are expressed in the testis, spleen, peripheral blood mononuclear cells (PBMC)s, adipose tissues, intestine, lung, liver, pancreas, ovary, thigh muscle, pectoralis muscle, eye, skin, subcutaneous adipose tissues, kidney, brain, heart, and uropygial gland [91]. Feline and canine soft tissue sarcoma as well as normal skin of felines and skeletal muscle of canines also showed the FFAR2 expression [92].…”

Molecular Mechanisms of Feline Cancers

“…In the study, researchers articulate three upregulated genes in particular, including fibroblast activation protein alpha (FAP-alpha), a cell surface serine protease, Wilms tumor 1 (WT1), a tumor suppressor and transcription factor, and preferentially expressed antigen in melanoma (PRAME), as well as downregulated tumor suppressors TP63, EPHA1, and DUSP26. In the study, GSK-1059615, an inhibitor of PI3K and mTOR in humans, was found to lower FISS cell growth, indicating PI3K and mTOR pathways could potentially be considered in new therapies [12].…”

“…Hyperthermia-induced gene immunotherapy with adenoviral feline IL-12 has been studied in spontaneous feline fibrosarcoma: intratumoral expression of the gene with limited systemic toxicity was achieved [85]. Enrichment of genes associated with IL-2 and IL-12 was also found in FISS cell lines [12].…”

“…FISS are not the only sarcoma associated with chronic inflammation, as feline ocular post-traumatic sarcomas are thought to be associated with chronic inflammation as well [11]. Chromosomal alterations as well as abnormal gene expression and mutations have been investigated in the past [12][13][14][15][16][17][18].…”