Mechanistic investigation of malignant rhabdoid childhood tumor using the Drosophila model

使用果蝇模型研究恶性横纹肌样儿童肿瘤的机制

• 批准号: 10215434
• 负责人: Wu-Min Deng
• 金额: $ 34.77万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215434
• 关键词: Adult; Biological Models; Cancer Biology; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Chromatin; Chromatin Remodeling Factor; Cytoplasm; Defect; Development; Developmental Biology; Drosophila genus; Epithelial; Event; Genes; Genetic; Growth; Homologous Gene; Hyperplasia; Investigation; MAPK8 gene; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Membrane; Modeling; Mosaicism; Mutation; Neoplasms; Nuclear; Pathway interactions; Pediatric Neoplasm; Play; Proteins; Recurrence; Rhabdoid Tumor; Role; SMARCB1 gene; SWI/SNF Family Complex; Signal Pathway; Signal Transduction; System; Testing; Tissues; Tumor Suppression; Tumor Suppressor Proteins; attenuation; early childhood; fly; imaginal disc; infancy; insight; neoplastic; notch protein; novel therapeutics; prevent; trafficking; tumor; tumorigenesis; tumorigenic

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.

项目摘要 恶性横纹肌肿瘤（MRTS）尤其是致命的癌症，主要出现在 婴儿期和幼儿。先前的研究表明，SMARCB1的损失，也称为 HSNF5/INI1本质上是该小儿癌中唯一的复发事件。自从 SMARCB1/HSNF5/INI是SWI/SNF染色质复合物的组成部分， MRT的原因通常与有缺陷的染色质构型有关。但是，突变 其他SWI/SNF复合部分在MRT中也没有发现，即使它们是 在各种成人癌症中普遍存在，表明Smarcb1与其他核心具有不同的作用 SWI/SNF复合物的组成部分。 SMARCB1损失的机制 因此，MRT的原因在很大程度上不清楚。在最新的研究中，使用了遗传处理 果蝇模型系统，我们发现fly smarcb1同源性SNR1，但没有其他 SWI/SNF复合物的成分在想象的上皮组织中充当肿瘤抑制剂。 我们进一步提出，SNR1通过维持正常内体阻止肿瘤发生 运输介导的信号网络通过其细胞质功能。根据这些 调查结果，我们将继续探索肿瘤发生中SNR1的机制。这 该提议中的中心假设是SNR1的胞质功能起着主要的肿瘤 抑制作用，从而破坏SNR1的细胞质功能会导致运输缺陷， 导致多种生长相关信号通路的放松管制，任何一个细胞自主 或非自主，以及SNR1缺失的肿瘤与相邻之间的相互作用 野生型组织中的增生会导致肿瘤发生的快速发展。我们将测试这个 假设通过追求以下特定目的：（1）确定细胞质SNR1如何 参与膜贩运。 （2）确定SNR1的损失如何导致肿瘤 过度生长的细胞自主。 （3）确定非自治的机制 SNR1的镶嵌损失过度生长。我们提出的研究的意义在于他们 与理解SNR1在肿瘤发生和科学领域中的机制有关的含义 例如细胞生物学，发育生物学和癌症生物学。使用遗传处理 确定SNR1在肿瘤抑制中的非常规功能的系统将提供 了解这种多效基因的丧失如何最终导致恶性小儿癌和 最终推动针对MRTS的新治疗途径的发展。