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 thePTPN11andKRASgenes 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 theFOXM1,AURKB,PLK1, andE2Fgenes, 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.
背景：组织细胞肉瘤（HS）是一种高度侵袭性的恶性肿瘤，其特征是狗和人类体内组织细胞的过度增殖。包括伯恩山犬（BMD）在内的一部分犬种显示出极高的HS患病率。我们及他人的先前研究已发现，约60%的犬HS中存在激活MAPK通路的PTPN11和KRAS基因的体细胞驱动突变。然而，其余40%的病例中尚未发现体细胞驱动突变。 目的：我们的目标是研究BMD中的HS，以深入了解该疾病的分子发病机制，并确定合理的治疗方法。 方法：在此，我们报告了对18个特征明确的BMD HS肿瘤组织以及三个HS细胞系进行的全转录组分析。 结果：我们的分析揭示了HS以及噬血性HS中涉及FOXM1、AURKB、PLK1和E2F基因的分子通路显著上调，为可能通过抑制剂靶向的通路提供了新信息。此外，我们记录了多个检查点基因的表达，提示了使用小分子抑制剂联合检查点抑制剂进行治疗的可能性。进一步，我们证明三个犬HS细胞系的转录组与犬患者肿瘤的转录组相似，进一步突显了它们在药物发现和疗效研究中的潜在用途。最后，我们首次证明极光激酶抑制剂能有效抑制HS细胞的体外生长，并与MAPK抑制显示出协同作用。 结论：本研究提供了迄今为止对犬HS转录组最详细的分析，突出了其发病机制中的关键通路，并为单一及联合治疗策略提出了新途径，这些发现可能对人类HS的治疗具有参考意义。
肿瘤(癌症)患者之家