Mechanistic investigation of malignant rhabdoid childhood tumor using the Drosophila model

项目总结 恶性横纹肌样肿瘤(Mrt)是一种特别致命的癌症，主要发生在 婴儿期和儿童期早期。先前的研究表明，SMARCB1，也被称为 HSNF5/INI1基本上是这种儿科癌症中唯一的复发事件。自.以来 SMARCB1/hSNF5/INI是SWI/SNF染色质重塑复合体的组成部分， MRTS的原因通常与染色质结构缺陷有关。然而，突变的基因 在MRT中没有发现其他SWI/SNF复杂组件，尽管它们是 在各种成人癌症中普遍存在，这表明SMARCB1与其他核心基因具有不同的作用 SWI/SNF综合体的组成部分。SMARCB1基因缺失的机制 因此，MRT的起因在很大程度上仍不清楚。在最近的一项研究中，使用了遗传上易驯服的 果蝇模型系统中，我们发现Fly SMARCB1与Snr1同源，而不是其他 SWI/SNF复合体的组成部分，在想象的上皮组织中发挥肿瘤抑制作用。 我们进一步认为，Snr1通过维持正常的内体来预防肿瘤的发生。 运输通过其细胞质功能介导的信号网络。在此基础上 随着研究结果的深入，我们将继续探索SNr1在肿瘤发生中的潜在机制。这个 这一建议的中心假设是SNr1的细胞质功能起着主要的肿瘤作用- 抑制作用，由此破坏SNr1的细胞质功能导致运输缺陷， 这导致多个与生长相关的信号通路放松调控，要么是细胞自主的 或非自主的，以及SNR1缺失的肿瘤与邻近肿瘤之间的相互作用 野生型组织的增殖导致肿瘤发生的快速进展。我们将对此进行测试 通过追求以下具体目标提出假说：(1)确定细胞质SNr1如何 参与了膜的贩运。(2)确定SNR1缺失如何导致肿瘤 细胞过度生长--自主生长。(三)确定非自治机制 SNR1的马赛克丢失后的过度生长。我们提出的研究的意义在于它们 与理解SNr1在肿瘤发生和科学领域中的机制有关的意义 如细胞生物学、发育生物学和癌症生物学。使用一种基因易驯服的 确定Snr1在肿瘤抑制中的非常规功能的系统将提供 关于这种多效性基因丢失如何导致儿童恶性癌症的见解，以及 最终推动针对MRT的新治疗途径的开发。

PROJECT SUMMARY Malignant rhabdoid tumors (MRTs) are especially lethal cancers that arise predominantly in infancy and early childhood. Previous studies revealed that loss of SMARCB1, also known as hSNF5/INI1, is essentially the sole recurrent event in this pediatric cancer. Since SMARCB1/hSNF5/INI is a component of the SWI/SNF chromatin-remodeling complex, the cause of MRTs is generally related to defective chromatin configuration. However, mutations of other SWI/SNF complex components have not been found in MRTs, even though they are prevalent in various adult cancers, suggesting SMARCB1 has a different role to other core components of the SWI/SNF complex. The mechanisms through which loss of SMARCB1 causes MRTs thus remains largely unclear. In a recent study using the genetically tractable Drosophila model system, we found that fly SMARCB1 homolog Snr1, but not other components of the SWI/SNF complex, acts as a tumor suppressor in imaginal epithelial tissues. We further suggested that Snr1 prevents tumorigenesis by maintaining normal endosomal trafficking-mediated signaling network through its cytoplasmic function. On the basis of these findings, we will continue to explore the mechanisms underlying Snr1 in tumorigenesis. The central hypothesis in this proposal is that cytoplasmic function of Snr1 plays a major tumor- suppressing role, whereby disruption of cytoplasmic function of Snr1 causes trafficking defects, which leads deregulation of multiple growth-related signaling pathways either cell-autonomously or non-autonomously, and the interaction between snr1-depleted neoplasm and neighboring hyperplasia in the wildtype tissue results in rapid progress of tumorigenesis. We will test this hypothesis by pursuing the following specific aims: (1) To determine how the cytoplasmic Snr1 is involved in membrane trafficking. (2) To determine how loss-of-snr1 results in neoplastic overgrowth cell-autonomously. (3) To determine the mechanisms of non-autonomous overgrowth upon mosaic loss of snr1. The significance of our proposed studies lies in their implications related to understanding mechanisms of Snr1 in tumorigenesis, and scientific fields such as cell biology, developmental biology, and cancer biology. The use of a genetic tractable system to determine the unconventional function of Snr1 in tumor suppression will provide insights into how loss of this pleiotropic gene can end up with a malignant pediatric cancer, and ultimately propel the development of new therapeutic avenues against MRTs.