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Dissecting the molecular and functional role of Sox2 in synovial sarcoma

剖析 Sox2 在滑膜肉瘤中的分子和功能作用

基本信息

批准号：
9237244
负责人：
Konrad Hochedlinger
金额：
$ 16.67万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-04 至 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9237244
关键词：
Ablation Alleles Automobile Driving Binding Biology Cell Line Cell Proliferation Cells ChIP-seq Chimeric Proteins Chromosomal translocation Chromosomes, Human, Pair 18 Complex Data Disease Embryo Event Gene Expression Gene Targeting Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomics Goals Growth Histologic Human In Vitro Lead Link Maintenance Malignant Neoplasms Mass Spectrum Analysis Molecular Mus Pathway interactions Patients Pattern Protein Subunits Proteins Reporter Reporting Role Sampling Signal Transduction Soft Tissue Neoplasms Somatic Cell Stem cells Systems Biology Testing Transgenic Organisms Undifferentiated activating transcription factor adult stem cell in vivo insight mouse model new therapeutic target outcome forecast pluripotency pre-clinical promoter public health relevance small molecule soft tissue synovial sarcoma transcriptome sequencing tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Synovial sarcoma (SS) is a common soft tissue malignancy that is routinely associated with a poor prognosis. The initiating event of SS is a single translocation t(X;18) resulting in the fusion of the SS18 gene on chromosome 18 to one of three closely related X-linked genes, termed SSX1, SSX2 and SSX4. A recent study demonstrated that endogenous SS18 and the SS18-SSX fusion protein are subunits of the SWI/SNF (BAF) complex, providing a possible mechanism by which this translocation may perturb gene expression and induce tumorigenesis. Of note, the pluripotency-associated gene Sox2 was recently shown to be expressed in cultured SS cell lines and Sox2 expression was reportedly required for continuous growth in vitro. Furthermore, we have found that Sox2 is upregulated in human SS as well as a mouse model of SS, and that the SS18-SSX-containing BAF complex specifically binds the Sox2 promoter. However, it remains unclear whether Sox2 is required for SS formation in vivo. Moreover, the mechanisms by which Sox2 expression contributes to synovial sarcoma has yet to be determined. Thus, the objective of this R21 application is to dissect the molecular and functional role of Sox2 in SS tumorigenesis in vivo, with the ultimate goal of identifying new therapeutic targets for treatment. We are proposing three independent aims to elucidate Sox2's role in SS biology by combining a preclinical mouse model with human samples. First, we will use transgenic Sox2 reporter and ablation alleles, generated by our lab, to record expression patterns of Sox2 and to assess if Sox2-positive cells act as synovial sarcoma stem cells. Second, we will test whether loss of Sox2 expression in mice is required for tumor formation. Lastly, we will determine genomic targets and binding partners of Sox2 by chromatin immunoprecipitation-sequencing and mass-spectrometry in order to define Sox2-specific transcriptional and signaling networks in synovial sarcoma. We will then use this data to initiate a pilot small molecule screen that targets the gene networks driven by Sox2. Altogether, this exploratory project will contribute to our understanding of Sox2's molecular and functional role in synovial sarcoma and may lead to new strategies to treat this malignancy by targeting stem cells or pathways that trigger differentiation.