Transcriptome analysis of canine histiocytic sarcoma tumors and cell lines reveals multiple targets for therapy
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ABSTRACT:
PROVIDER: PRJNA1215992 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32133257_1.fastq.gz | Fastqsanger.gz | |||
| SRR32133257_2.fastq.gz | Fastqsanger.gz | |||
| SRR32133258_1.fastq.gz | Fastqsanger.gz | |||
| SRR32133258_2.fastq.gz | Fastqsanger.gz | |||
| SRR32133259_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
2025-03-18 | GSE288068 | GEO
Project description:The objective of this study was to compare the transcriptomes of uninfected DH82 cells, a canine histiocytic sarcoma cell line, with DH82 cells, persistently infected with the Onderstepoort strain of canine distemper virus in order to identify effects of canine distemper virus infection upon the transcriptome of this tumor cell line and hereby draw conclusions on possible paramyxovirus-induced oncolytic mechanisms
2016-12-02 | E-MTAB-3942 | biostudies-arrayexpress
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.
2013-08-07 | E-GEOD-45832 | biostudies-arrayexpress
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.
2013-08-07 | GSE45832 | GEO
Project description:Molecular Genetics of Secondary Histiocytic/Dendritic Sarcoma
| PRJNA593082 | ENA
Project description:Molecular Genetics of Secondary Histiocytic/Dendritic Sarcoma
| PRJNA593083 | ENA
Project description:Background Leukemia/lymphoma cell lines have been critical in the investigation of the pathogenesis and therapy of hematological malignancies. While human LL cell lines have generally been found to recapitulate the primary tumors from which they were derived, appropriate characterization including cytogenetic and transcriptional assessment is crucial for assessing their clinical predictive value. Results In the following study, five canine LL cell lines, CLBL-1, Ema, TL-1 (Nody-1), UL-1, and 3132, were characterized using extensive immunophenotyping, karyotypic analysis, oligonucleotide array comparative genomic hybridization (oaCGH), and gene expression profiling. Genome-wide DNA copy number data from the cell lines were also directly compared with 299 primary canine round cell tumors to determine whether the cell lines represent primary tumors, and, if so, what subtype each most closely resembled. Discussion Based on integrated analyses, CLBL-1 was classified as B-cell lymphoma, Ema and TL-1 as T-cell lymphoma, and UL-1 as T-cell acute lymphoblastic leukemia. 3132, originally classified as a B-cell lymphoma, was reclassified as a histiocytic sarcoma based on characteristic cytogenomic properties. In combination, these data begin to elucidate the clinical predictive value of these cell lines which will enhance the appropriate selection of in vitro models for future studies of canine hematological malignancies. GEP using GeneChip Canine Genome 2.0 array (Affymetrix, Santa Clara, CA) Five canine lymphoid cell lines analyzed
2016-08-19 | E-GEOD-85720 | biostudies-arrayexpress