Molecular Modeling of Pediatric Skeletal Muscle Tumors

儿童骨骼肌肿瘤的分子模型

基本信息

批准号：
7751314
负责人：
Corinne Mary Linardic
金额：
$ 29.13万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-01-01 至 2013-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7751314
关键词：
Accounting Address Age Alveolar Apoptosis Appearance Behavior Biochemical Biological Assay Bypass Catalytic Domain Cell Line Cell Proliferation Cells Child Childhood Collection Complement DNA Tumor Viruses Development Disease Disease model Embryonal Rhabdomyosarcoma Enzymes Event FOXO1A gene GTP-Binding Proteins Growth HRAS gene Histologic Human Immunoblotting Immunodeficient Mouse Investigation Knowledge Light Malignant - descriptor Malignant Childhood Neoplasm Malignant Neoplasms Mediating Microscopic Modeling Molecular Models Monitor Muscle Fibers Mutation Myoblasts Names Oncogenes Oncogenic Outcome PAX3 gene Pathway interactions Patients Phenotype Population Proteins Ras Signaling Pathway Receptor Protein-Tyrosine Kinases Research Rhabdomyosarcoma Role Series Signal Transduction Simian virus 40 Skeletal Muscle Skeletal Muscle Neoplasm Solid Neoplasm TP53 gene Telomerase Testing Tumor Suppressor Proteins Up-Regulation Xenograft procedure angiogenesis base cancer cell cell transformation fetal fusion gene gain of function high risk in vivo insight light microscopy loss of function molecular modeling neoplastic cell new therapeutic target overexpression postnatal human public health relevance research study sarcoma senescence skeletal muscle differentiation soft tissue standard care transgene expression tumor tumor xenograft tumorigenesis tumorigenic vector

项目摘要

DESCRIPTION (provided by applicant): Rhabdomyosarcoma (RMS) is a heterogeneous collection of cancers demonstrating varying degrees of skeletal muscle differentiation. Although accounting for ~8% of pediatric malignant solid tumors, RMS is the most common soft tissue sarcoma in children younger than 14 years. The two major histologic subtypes of RMS are embryonal (eRMS) and alveolar (aRMS). High risk patients have a 5-year survival of 30%, and outcome is very poor for children whose tumors express the PAX3-FKHR fusion gene; when metastatic, their 5-year survival is <8%. This signature genetic change is found only in aRMS and considered a tumor-specific oncogene, but has no molecularly targeted treatment. To address gaps in knowledge of RMS, we have created a new model for this disease based on the conversion of primary human skeletal muscle cells to their tumorigenic counterpart, using a defined set of genetic changes. Using this model, we found that human skeletal muscle myoblasts may be converted to cells that generate tumors mimicking RMS when tested as xenografts in immunodeficient mice. Having established that primary human cells of skeletal muscle origin can give rise to RMS, we studied the repercussions of expressing PAX3-FKHR in them, and discovered two phenotypes that may underlie its oncogenic behavior. First, when PAX3-FKHR was stably expressed as an early genetic change, it enabled bypass of the senescence checkpoint and served as an initiating oncogenic hit for the development of skeletal muscle tumors. Second, when PAX3-FKHR was stably expressed as a late genetic change, it shortened the latency of in vivo tumor formation from 11 to 2 weeks, possibly through activation of the Ras pathway, since in control experiments PAX3-FKHR could functionally substitute for the RAS oncogene. In this proposal, we wish to understand how PAX3-FKHR enables bypass of the senescence checkpoint, and how it accelerates tumorigenesis in previously transformed cells. To accomplish this, we will (1) examine candidate proteins that are downstream of PAX3-FKHR for their role in overcoming the senescence checkpoint, using both gain-of-function and loss-of-function approaches, and (2) examine the accelerated tumor cells for enhanced self-sufficiency in growth signaling, apoptosis, and/or angiogenesis, and the role of the Ras pathway in this PAX3-FKHR-augmented tumorigenesis. The accomplishment of these aims will provide insight into the genesis of this pediatric malignancy, and provide new therapeutic targets for study. In addition, this genetically defined model will serve as a template for the systematic investigation of other human sarcomas. PUBLIC HEALTH RELEVANCE: This research uniquely models the series of oncogenic events causing the pediatric cancer rhabdomyosarcoma. It is expected to yield insight into the genesis of this cancer, provide new therapeutic targets for study, and serve as a template for the systematic analysis of other human sarcomas.

描述（由申请人提供）：横纹肌肉瘤（RMS）是癌症的异质集合，表现出不同程度的骨骼肌分化。尽管占小儿恶性实体瘤的约8％，但RMS是14岁以下儿童中最常见的软组织肉瘤。 RMS的两个主要组织学亚型是胚胎（ERMS）和肺泡（臂）。高风险患者的5年生存率为30％，对于肿瘤表达PAX3-FKHR融合基因的儿童的结果非常差。当转移性的5年生存率<8％。这种特征性的遗传变化仅在手臂上发现，并被认为是肿瘤特异性癌基因，但没有分子靶向治疗。为了解决RMS知识的差距，我们使用定义的一组遗传变化基于原发性人类骨骼肌细胞向其致瘤性对应物创建了一种新模型。使用此模型，我们发现人类骨骼肌成肌细胞可能会转化为细胞，该细胞在免疫缺陷小鼠中以异种移植作用测试时会产生模仿RMS的肿瘤。确定骨骼肌起源的原代人细胞可以引起RMS，我们研究了在其中表达PAX3-FKHR的影响，并发现了两种可能是其致癌行为的表型。首先，当Pax3-FKHR被稳定地表达为早期遗传变化时，它可以绕开衰老检查点，并作为骨骼肌肿瘤发展的启动致癌命中率。其次，当Pax3-FKHR稳定地表示为遗传变化时，它缩短了体内肿瘤形成的潜伏期从11到2周，可能是通过RAS途径的激活，因为在控制实验中，PAX3-FKHR可以在功能上替代Ras Oncogene。在此提案中，我们希望了解PAX3-FKHR如何实现衰老检查点的旁路，以及它如何加速先前转化的细胞中的肿瘤发生。为此，我们将（1）使用功能障碍和功能丧失方法来检查PAX3-FKHR下游的候选蛋白在克服衰老检查点中的作用，以及（2）检查加速肿瘤细胞在增强的生长信号传导，脾脏，/或触角的自由度，以及在这种情况下增强的，以及在这种情况下，以及在这种情况下，以及在这种情况下，以及在这种情况下的起作用，在这种情况下，在这种情况下，在这种情况下，在这种情况下构成了RAS的作用。 PAX3-FKHR肿瘤发生。这些目标的实现将为这种儿科恶性肿瘤的起源提供见解，并为研究提供了新的治疗靶标。此外，这种遗传定义的模型将作为对其他人类肉瘤进行系统研究的模板。公共卫生相关性：这项研究独特地模拟了导致小儿横纹肌肉瘤的一系列致癌事件。预计它将深入了解该癌症的起源，为研究提供新的治疗靶标，并作为对其他人类肉瘤进行系统分析的模板。