Determining the Mechanism of Transformation for Rhabdomyosarcoma

确定横纹肌肉瘤的转化机制

• 批准号: 10411905
• 负责人: Madeline Bush Searcy
• 金额: $ 4.28万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411905
• 关键词: Adipose tissue; Alleles; Biological Assay; Bladder; Blood Vessels; Cell Lineage; Cells; Child; Clinical Trials; Data; Development; Embryonal Rhabdomyosarcoma; Endothelial Cells; Endothelium; Enterobacteria phage P1 Cre recombinase; Event; Genes; Genetically Engineered Mouse; Head and Neck Muscle; Head and neck structure; In Vitro; Lead; Life; Location; Maintenance; Modeling; Mus; Muscle; Muscle Cells; Muscle Development; Neck; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacotherapy; Play; Proliferating; Prostate; Proteins; Publications; Radiation; Research Support; Resistance; Rhabdomyosarcoma; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Soft tissue sarcoma; Solid Neoplasm; Sonic Hedgehog Pathway; Specific qualifier value; Survival Rate; Testing; Tissues; Transgenic Mice; Work; biliary tract; cell type; chemotherapy; experimental study; high risk; improved; induced pluripotent stem cell; insight; knock-down; loss of function; mouse model; mutant; myogenesis; neoplastic cell; overexpression; patient stratification; postnatal; prevent; progenitor; promoter; risk stratification; small hairpin RNA; transcription factor; transdifferentiation; tumor; tumor initiation; tumorigenesis

ABSTRACT Rhabdomyosarcoma (RMS) is an aggressive, soft-tissue sarcoma in children. While many clinical trials have worked to improve patient outcomes, the 3-year survival rate for high-risk children hasn’t risen above 20% for the past three decades. Children with RMS undergo surgery, radiation, and chemotherapy, which lead to serious life-long consequences. RMS is thought to arise from a block in myogenesis which prevents normal skeletal muscle development leading to tumor formation. However, RMS can develop in tissues devoid of skeletal muscle such as the urinary bladder, prostate, and biliary tree, suggesting that RMS may have an alternative cell of origin other than a myogenic progenitor. A recent publication by our lab, Drummond et al., identified endothelial cells as a candidate cell of origin for RMS. Our genetically engineered mouse model expresses a constitutively active Smoothened (SmoM2) allele in cells expressing Cre recombinase driven by the adipose protein 2 (aP2) promoter. 50% of these mice develop RMS specifically restricted to the neck by 28 days of life. aP2-Cre is expressed by multiple cell types including endothelial cells, but not muscle cells. This indicates that RMS can arise from non- myogenic cells, however many questions still remain. My proposed project focuses on understanding the role of SmoM2 in tumorigenesis and proliferation, and the downstream signaling that causes a myogenic fate switch in endothelial progenitors. To determine whether continued SmoM2 is required for tumor maintenance and proliferation, I will culture tumor cells in vitro as tumor spheres and evaluate the ability of tumor spheres to passage with SmoM2 knocked down. The second aspect of my project is to identify the mechanism of cellular reprogramming leading to RMS formation specifically in the neck. Preliminary data from our lab, supported by research from other groups, shows that head and neck muscle specification transcription factors such as Tbx1, Pitx2, Tcf21 and Musculin are increased upon SmoM2 expression. To determine the mechanism of cellular reprogramming initiated by SmoM2 expression in aP2-lineage cells, our lab generated a transgenic mouse that conditionally overexpresses Tbx1 and acquired another that has conditional deletion of the Tbx1 allele, which allows us to ascertain whether Tbx1 is sufficient and necessary to cause tumorigenesis. Understanding the mechanistic basis for reprogramming in RMS will not only help us create more directed therapies for these patients, but also suggests that similar reprogramming events may contribute to other solid tumors.

摘要