A novel mouse model of testicular granulosa cell tumors

标题：睾丸颗粒细胞瘤的新型小鼠模型 项目摘要 尽管I期颗粒细胞瘤（GCT）的5年生存率相对较高， 患者，预后不良与晚期肿瘤患者相关，证明需要 来研究这种不明确的肿瘤。值得注意的是，GCT也可能来自睾丸， 低发病率。因此，动物模型是有用的，以研究这种疾病的发病机制。 使用Amhr 2-Cre过度激活转化生长因子β（TGFβ）受体1（TGFBR 1）， 靶向小鼠颗粒细胞引起卵巢GCT的发展。结果发现 雄性小鼠在幼年时发生睾丸GCT。令人兴奋的表型表现 这些小鼠睾丸中的GCT提出了一个问题，即TGFβ信号转导的失调如何影响 促进睾丸GCT形成。核心假设是TGFβ的失调 信号转导改变了支持细胞的分化程序，促进了支持细胞的转分化。 支持细胞到恶性颗粒细胞是GCT的特征。这个假设是基于 令人信服的遗传证据，并将在一个单一的目标进行测试，通过确定机制 TGFBR 1的组成性激活导致睾丸GCT发育的基础。 将利用转录组学和蛋白质组学分析相结合的综合方法， 解决提出的问题。这一应用的结果预计将提供一个范式转变 为了了解性腺肿瘤发生并揭示生长因子信号传导之间的新联系， 细胞命运改变和肿瘤发生。因此，完成这项建议将有一个 对睾丸GCT的病因有重要影响。这些发现具有潜在的诊断和 性索间质肿瘤的治疗价值。

Title: A novel mouse model of testicular granulosa cell tumors PROJECT SUMMARY Despite the relatively high 5-year survival rate of granulosa cell tumors (GCTs) in stage I patients, poor prognosis is associated with patients at advanced tumor stage, justifying the need to study this type of poorly defined tumors. Of note, GCTs may also arise from the testis with low incidence. Thus, animal models are useful to investigate the pathogenesis of this disease. Overactivation of transforming growth factor β (TGFβ) receptor 1 (TGFBR1) using Amhr2-Cre to target mouse granulosa cells provokes the development of ovarian GCTs. It was found that male mice develop testicular GCTs at an early age. The exciting phenotypic manifestation of GCTs in the testes of these mice raised the question of how dysregulated TGFβ signaling promotes testicular GCT formation. The central hypothesis is that dysregulation of TGFβ signaling alters the differentiation program of Sertoli cells, promoting the transdifferentiation of Sertoli cell to malignant granulosa cells characteristic of GCTs. This hypothesis is based on compelling genetic evidence, and will be tested in a single aim by identifying mechanistic underpinnings of testicular GCT development resulting from constitutive activation of TGFBR1. A comprehensive approach combining transcriptomic and proteomic analyses will be utilized to address the posed question. Results of this application are expected to provide a paradigm shift for understanding gonadal tumorigenesis and reveal a novel link among growth factor signaling, cell fate alteration, and oncogenesis. Therefore, completion of this proposal will have a significant impact on the etiology of testicular GCTs. The findings have potential diagnostic and therapeutic value for sex cord-stromal tumors.