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Defining the non-myogenic origins of pediatric rhabdomyosarcoma

定义小儿横纹肌肉瘤的非肌源性起源

基本信息

批准号：
9307162
负责人：
Mark Edward Hatley
金额：
$ 41.06万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-05 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9307162
关键词：
Adipose tissue Alleles Anatomy Anterior Automobile Driving Bladder Cell Lineage Cell Proliferation Cells Child Childhood Childhood Rhabdomyosarcoma Chromatin Clinical Trials Development Developmental Process Embryo Embryonic Development Employee Strikes Endothelial Cells Enterobacteria phage P1 Cre recombinase Environment Epigenetic Process Event FOXO1A gene Gene Expression Gene Fusion Genes Genetic Genetically Engineered Mouse Goals Head and neck structure Hindlimb Histologic Histology Label Laboratories Life Location Malignant Neoplasms Modeling Mus Muscle Neck Oncogenes Oncogenic Operative Surgical Procedures PAX3 gene PAX7 gene Pathway interactions Pharmacotherapy Population Prognostic Factor Prostate Proteins Radiation Reporter Reporting Research Personnel Rhabdomyosarcoma Skeletal Muscle Soft tissue sarcoma Specific qualifier value Specificity Stem cells Suggestion Tamoxifen Testing Time Tissues Transplantation Tumor Initiators Work aggressive therapy base biliary tract cell type chemotherapy design disorder risk early onset experimental study genetic signature high risk insight mouse model novel outcome forecast permissiveness progenitor promoter tumor tumorigenesis

项目摘要

Project Summary/Abstract Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children and is a highly aggressive form of cancer. Children with high-risk disease suffer from a 3-year survival of only 20% despite very aggressive therapy with chemotherapy, surgery and radiation. Despite rigorous clinical trials, the survival of children suffering from high-risk rhabdomyosarcoma has not significantly changed over the last three decades. RMS can occur at locations throughout the body with nearly 40% of tumors occurring in the head and neck. Tumor location and fusion status are key prognostic factors. RMS histology resembles developing skeletal muscle and has been speculated to originate from genetically compromised skeletal muscle progenitors. However, the genes that control RMS development and specify location remain elusive. RMS also occurs in tissues devoid of skeletal muscle such as the urinary bladder, prostate, and biliary tree suggesting the possibility of origins outside of the skeletal muscle lineage. Currently, the cell of origin and the factors that specify RMS location and thus prognosis are unknown. Our long-term goal is to elucidate the mechanisms that determine the basis for developmental arrest in RMS and design novel, directed drug therapies for RMS. Previously, we reported a novel genetically engineered mouse model of fusion-negative RMS (FN-RMS) resulting from activation of a conditional, constitutively active Smoothened (SmoM2) allele by Cre recombinase expressed from the adipose protein 2 (aP2) promoter. In our model, 50% of the mice develop visible tumors by 28 days of life that are anatomically restricted to the neck. Perhaps the most intriguing aspect of our mouse FN-RMS model is the suggestion that RMS originates outside of the muscle, as aP2-Cre is not expressed in skeletal muscle. The objective of this proposal is to leverage the early onset and anatomic restriction to the neck to identify the cell of origin and factors that specify RMS location. To accomplish this objective we propose the following Specific Aims: 1) Determine developmental timing and location for oncogenesis in Shh- driven FN-RMS. 2) Identify the cell of origin of FN-RMS in aP2-Cre;SmoM2 mice. 3) Define regional specificity of FN-RMS. Using transplantation, we will determine whether the location specificity is driven cell autonomously on non-cell autonomously. We will isolate aP2-labeled, early developmental cells from normal mice and tumor mice to define how gene expression, epigenetic and chromatin accessibility differences between these populations contribute to the location and timing specificity. We will leverage our unique FN- RMS mouse model to identify the cell of origin and provide insights into the developmental events promoting FN-RMS formation. This work will help illuminate how the major developmental Shh pathway contributes to the specificity of cell types in the head and neck allowing for FN-RMS. Given the wide spectrum of RMS tumor locations and how location dictates prognosis we speculate that the varied cell of origin will further refine prognosis along with histology and further genetic characterization.

项目总结/文摘