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Transcriptome analysis of canine histiocytic sarcoma tumors and cell lines reveals multiple targets for therapy

ABSTRACT: Histiocytic sarcoma (HS) is a highly aggressive malignancy characterized by excessive proliferation of histiocytes in dogs and humans. A subset of dog breeds, including the Bernese mountain dog (BMDs) show a remarkably high prevalence of HS, thus provide opportunities for insight into the molecular pathogenesis of the disease. Previous work by our lab and others has identified somatic driver mutations of HS in the PTPN11 and KRAS genes that activate the MAPK pathway in about 60% of canine HS cases. However, no somatic driver mutations have been identified in the remaining 40%. Here, we report our whole transcriptome analysis of eighteen well-characterized BMD HS tumor tissues, as well as three HS cell lines, allowing us to gain further insight into the molecular basis of HS tumorigenesis. Our analysis reveals significant upregulation of molecular pathways involving the FOXM1, AURKB, PLK1, and E2F genes, providing new information regarding pathways that may be targeted with inhibitors. In addition, we document the expression of multiple checkpoint genes, suggesting the option of treatment with small molecule inhibitors together with checkpoint inhibitors. Further, we show that the transcriptomes of three canine HS cell lines mirror those of canine patient tumors, further highlighting their potential use in drug efficacy studies. Finally, we demonstrate, for the first time, that aurora kinase inhibitors are effective in curtailing growth of HS cells in vitro and show synergism with MAPK inhibition. This study provides the most detailed analysis of the canine HS transcriptome to date, highlighting key pathways in its pathogenesis and suggesting new avenues for both single and combination treatment strategies which may be pertinent to treatment of human HS.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE288068 | GEO | 2025/03/18

REPOSITORIES: GEO

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Project description:Background: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors has value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Methods: Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. Results: QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. Conclusions: This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Extraploration of this downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human. Microarray expression dataset including STHS: Soft Tissue (localized) Histiocytic Sarcoma; VHS: Visceral (disseminated)Histiocytic Sarcoma; together with normal spleen (NS) samples. Comparisons were analysed in dyeswap on a 2-color platform against a common reference sample, consisting of a multitude of canine organs, including liver, spleen, kidney, lung, hart, intestine and bone.

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Transcriptome analysis of canine histiocytic sarcoma tumors and cell lines reveals multiple targets for therapy

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