Oncogenic mechanism of Sox2 in Rb-deficient tumors

Sox2 在 Rb 缺陷肿瘤中的致癌机制

• 批准号: 10439599
• 负责人: Michael S Kareta
• 金额: $ 37.74万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-23 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439599
• 关键词: 3-Dimensional; ATAC-seq; Adult; Affect; Automobile Driving; Binding; Biological Assay; Cancer Intervention; Cell Proliferation; Cells; ChIP-seq; Child; Child Health; Data; Development; Enhancers; Epigenetic Process; Future; Gene Expression; Genes; Genetically Engineered Mouse; Genomics; Goals; Growth; Histones; Homeostasis; Human; Human Cell Line; Individual; Investigation; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of pituitary gland; Mediating; Mus; Neuroendocrine Cell; Neuroendocrine Tumors; Normal tissue morphology; Oncogenes; Oncogenic; Organoids; Pathway interactions; Pediatric Neoplasm; Play; Post-Translational Protein Processing; Primary Neoplasm; Proteins; Regulation; Repression; Retinoblastoma; Role; Solid Neoplasm; Testing; Therapeutic; Tissues; Transplantation; Tumor Cell Line; Tumor Suppression; Tumor Suppressor Proteins; United States; Up-Regulation; base; cancer initiation; cancer therapy; causal variant; cell growth regulation; cohesion; epigenetic regulation; experimental study; fascinate; gene network; innovation; knock-down; lung small cell carcinoma; novel; overexpression; pluripotency; progenitor; rare cancer; recruit; retinoblastoma tumor suppressor; transcription factor; transcriptome sequencing; tumor; tumor initiation; tumor progression

PROJECT SUMMARY The retinoblastoma tumor suppressor (Rb) is a central gene that has been implicated in the formation of multiple solid tumors. It does so by both the regulation of cellular proliferation and driving cellular differentiation to establish cellular identity. Lack of Rb then leads to cancer, yet the mechanisms which underlie the pro- oncogenic consequences of Rb-loss are still not fully understood. A novel role for Rb in the repression of essential pluripotency genes has been identified and this repression of pluripotency serves to restrict cellular plasticity and tumor formation. One of the Rb-regulated pluripotency genes identified was Sox2 which can indeed be oncogenic in some cellular contexts. However, the mechanisms of Sox2 oncogenic activity in tumors formed by Rb-loss are currently unclear. This proposal is based upon the hypothesis that upregulation of Sox2 after Rb-loss is a crucial oncogenic driver in the Rb-loss initiated tumors, and is due in part to the ability of Sox2 to enhance cellular plasticity and upregulate progenitor-state pathways. To investigate this hypothesis, this project will aim to establish the role of Sox2 in cancer initiation upon loss of Rb. This will be achieved by the utilization of genetically engineered mouse models which will test if Sox2 is required for the initiation and growth of multiple Rb-loss initiated tumors. The role for Sox2 in the maintenance and propagation of these tumors will be studied by standard growth and transplantation assays using established mouse and human cell lines. Finally, this project will aim to elucidate the oncogenic mechanisms of Sox2 in cancer. Genomic-scale investigations into the gene network regulated by Sox2 will be examined by ChIP-seq of Sox2 in tumor cell lines in conjunction with RNA-seq, ChIP-seq of modified histones, and ATAC-seq to identify the means of regulation of the greater Sox2 network. Downstream targets will be validated by their overexpression or knockdown in tumor cell lines or GEMMs. This investigation will identify the extent that Rb-loss initiated tumors are dependent upon Sox2 and the mechanisms by which Sox2 participates in tumor development by the elucidation of the broader Sox2 network in cancer. This will serve to build a cohesive gene expression network to describe the oncogenic effects that follow Rb-loss and describe how these tumors are formed. Understanding this downstream Sox2 network may provide novel targets for the treatment of these tumors and will provide a groundwork for future investigations into the development of cancer therapeutics.

项目摘要 视网膜母细胞瘤肿瘤抑制因子（RB）是一种中心基因，与形成有关 多个实体瘤。它通过调节细胞增殖和驱动细胞分化来做到这一点 建立细胞身份。不足RB会导致癌症，但其基于亲癌的机制 RB损失的致癌后果仍未完全了解。 RB在镇压中的新作用 已经鉴定出必需的多能基因，这种对多能性的抑制作用可限制细胞 塑性和肿瘤形成。鉴定出RB调节的多能基因之一是Sox2，可以 在某些细胞环境中确实是致癌的。但是，肿瘤中SOX2致癌活性的机制 目前尚不清楚由RB损失组成。该提议基于以下假设：Sox2上调 在RB损坏是RB损伤引发的肿瘤中的至关重要的致癌驱动器之后，部分原因是 SOX2增强细胞可塑性并上调祖细胞状态途径。为了研究这一假设， 该项目将旨在在失去RB时确定Sox2在癌症启动中的作用。这将通过 基因工程鼠标模型的利用，该模型将测试是否需要Sox2进行启动和 多个RB损伤的生长引发了肿瘤。 Sox2在维护和传播中的作用 使用已建立的小鼠和人类细胞的标准生长和移植测定将研究肿瘤 线。最后，该项目将旨在阐明癌症中SOX2的致癌机制。基因组规模 对SOX2调节的基因网络的研究将通过SOX2的chip-Seq在肿瘤细胞中检查 与RNA-seq，修饰组蛋白的芯片隔离和ATAC-SEQ结合使用的线条，以识别 更大的Sox2网络的调节。下游目标将通过其过表达或 在肿瘤细胞系或GEMM中敲低。这项研究将确定RB损坏引发肿瘤的程度 取决于Sox2和Sox2参与肿瘤发展的机制 在癌症中阐明更广泛的SOX2网络。这将有助于建立一个凝聚力的基因表达网络 描述遵循RB损坏的致癌作用并描述如何形成这些肿瘤。 了解这种下游SOX2网络可能会为治疗这些肿瘤的治疗提供新的目标 将为将来研究癌症治疗剂的发展提供基础。