Alexander I Engleberg, Ya-Ting Yang, Peter Z Schall, Marilia Takada, Tuddow Thaiwong-Nebelung, Jacquelyn M Evans, Elaine A Ostrander, Vilma Yuzbasiyan-Gurkan
{"title":"犬组织细胞肉瘤肿瘤和细胞系转录组分析揭示了多个治疗靶点","authors":"Alexander I Engleberg, Ya-Ting Yang, Peter Z Schall, Marilia Takada, Tuddow Thaiwong-Nebelung, Jacquelyn M Evans, Elaine A Ostrander, Vilma Yuzbasiyan-Gurkan","doi":"10.3390/cancers17060954","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background</b>: Histiocytic sarcoma (HS) is a highly aggressive malignancy characterized by the excessive proliferation of histiocytes in dogs and humans. A subset of dog breeds, including the Bernese Mountain Dog (BMD), show a remarkably high prevalence of HS. Previous work by us and others has identified somatic driver mutations of HS in the <i>PTPN11</i> and <i>KRAS</i> genes that activate the MAPK pathway in about 60% of canine HS. However, no somatic driver mutations have been identified in the remaining 40%. <b>Objectives</b>: Our goals are to study HS in BMDs to gain insight into the molecular pathogenesis of the disease, and identify rational approaches to therapy. Methods: Here, we report our whole transcriptome analysis of 18 well-characterized BMD HS tumor tissues, as well as three HS cell lines. <b>Results</b>: Our analysis reveals the significant upregulation of molecular pathways involving the <i>FOXM1</i>, <i>AURKB</i>, <i>PLK1</i>, and <i>E2F</i> genes, in HS as well as hemophagocytic HS, 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 discovery and efficacy studies. Finally, we demonstrate, for the first time, that aurora kinase inhibitors are effective in curtailing the growth of HS cells in vitro and show synergism with MAPK inhibition. <b>Conclusions</b>: 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 the treatment of human HS.</p>","PeriodicalId":9681,"journal":{"name":"Cancers","volume":"17 6","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940154/pdf/","citationCount":"0","resultStr":"{\"title\":\"Transcriptome Analysis of Canine Histiocytic Sarcoma Tumors and Cell Lines Reveals Multiple Targets for Therapy.\",\"authors\":\"Alexander I Engleberg, Ya-Ting Yang, Peter Z Schall, Marilia Takada, Tuddow Thaiwong-Nebelung, Jacquelyn M Evans, Elaine A Ostrander, Vilma Yuzbasiyan-Gurkan\",\"doi\":\"10.3390/cancers17060954\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background</b>: Histiocytic sarcoma (HS) is a highly aggressive malignancy characterized by the excessive proliferation of histiocytes in dogs and humans. A subset of dog breeds, including the Bernese Mountain Dog (BMD), show a remarkably high prevalence of HS. Previous work by us and others has identified somatic driver mutations of HS in the <i>PTPN11</i> and <i>KRAS</i> genes that activate the MAPK pathway in about 60% of canine HS. However, no somatic driver mutations have been identified in the remaining 40%. <b>Objectives</b>: Our goals are to study HS in BMDs to gain insight into the molecular pathogenesis of the disease, and identify rational approaches to therapy. Methods: Here, we report our whole transcriptome analysis of 18 well-characterized BMD HS tumor tissues, as well as three HS cell lines. <b>Results</b>: Our analysis reveals the significant upregulation of molecular pathways involving the <i>FOXM1</i>, <i>AURKB</i>, <i>PLK1</i>, and <i>E2F</i> genes, in HS as well as hemophagocytic HS, 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 discovery and efficacy studies. Finally, we demonstrate, for the first time, that aurora kinase inhibitors are effective in curtailing the growth of HS cells in vitro and show synergism with MAPK inhibition. <b>Conclusions</b>: 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 the treatment of human HS.</p>\",\"PeriodicalId\":9681,\"journal\":{\"name\":\"Cancers\",\"volume\":\"17 6\",\"pages\":\"\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-03-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940154/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cancers\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3390/cancers17060954\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancers","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3390/cancers17060954","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
Transcriptome Analysis of Canine Histiocytic Sarcoma Tumors and Cell Lines Reveals Multiple Targets for Therapy.
Background: Histiocytic sarcoma (HS) is a highly aggressive malignancy characterized by the excessive proliferation of histiocytes in dogs and humans. A subset of dog breeds, including the Bernese Mountain Dog (BMD), show a remarkably high prevalence of HS. Previous work by us 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. However, no somatic driver mutations have been identified in the remaining 40%. Objectives: Our goals are to study HS in BMDs to gain insight into the molecular pathogenesis of the disease, and identify rational approaches to therapy. Methods: Here, we report our whole transcriptome analysis of 18 well-characterized BMD HS tumor tissues, as well as three HS cell lines. Results: Our analysis reveals the significant upregulation of molecular pathways involving the FOXM1, AURKB, PLK1, and E2F genes, in HS as well as hemophagocytic HS, 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 discovery and efficacy studies. Finally, we demonstrate, for the first time, that aurora kinase inhibitors are effective in curtailing the growth of HS cells in vitro and show synergism with MAPK inhibition. Conclusions: 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 the treatment of human HS.
期刊介绍:
Cancers (ISSN 2072-6694) is an international, peer-reviewed open access journal on oncology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.