Bone and Soft Tissue Tumor Etiology: Role and Function of TRE17/USP6

骨和软组织肿瘤病因学：TRE17/USP6 的作用和功能

• 批准号: 8883418
• 负责人: Margaret Mary Chou
• 金额: $ 26.16万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883418
• 关键词: Accounting; Adult; Alveolar Rhabdomyosarcoma; Amalgam; Anatomy; Aneurysmal Bone Cysts; Biology; Bone Tissue; Carcinoma; Cell Culture Techniques; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Childhood; Clinical; Collaborations; Connective and Soft Tissue Neoplasm; Cytogenetics; Data; Development; Disease; Epithelial; Etiology; Event; Fasciitis; Gene Expression Profile; Genetic Engineering; Goals; Growth; Health; Human; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Lead; Maintenance; Malignant - descriptor; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Modeling; Modification; Molecular; Molecular Genetics; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neoplasms; Oncogenes; Operative Surgical Procedures; Pathogenesis; Pathologist; Pathway interactions; Patients; Phosphotransferases; Primary Neoplasm; Recurrence; Rhabdomyosarcoma; Role; STAT3 gene; Sampling; Signal Transduction; Soft Tissue Neoplasms; Survival Rate; Symptoms; Testing; Therapeutic Intervention; Ubiquitin; Work; Xenograft Model; Xenograft procedure; activating transcription factor; angiogenesis; base; bioluminescence imaging; cancer stem cell; cancer type; complement pathway; effective therapy; human USP6 protein; in vitro Assay; in vivo; inhibitor/antagonist; insight; molecular oncology; mortality; mouse model; neoplastic cell; novel; novel strategies; novel therapeutics; oncology; overexpression; paracrine; promoter; research study; response; transcription factor; tumor; tumor microenvironment; tumorigenesis

DESCRIPTION (provided by applicant): Bone and soft tissue tumors (BSTTs) are important yet understudied entities in human oncology. Our incomplete understanding of their pathogenesis has limited development of effective therapies. This proposal focuses on the role of TRE17/ubiquitin-specific protease 6 (USP6), in BSTT pathogenesis. Recurrent translocations of TRE17 occur in two BSTTs, aneurysmal bone cyst (ABC) and nodular fasciitis (NF), resulting in overexpression of wild type TRE17. TRE17 overexpression also arises selectively in other BSTTs, particularly the highly lethal alveolar rhabdomyosarcoma (ARMS). TRE17 potently activates the transcription factors NFkB and STAT3, in a manner dependent on its USP activity. Both NFkB and STAT3 are frequently dysregulated in cancer, often coordinately, to promote tumor cell survival and proliferation, inflammation, and angiogenesis. This proposal will test whether NFkB and STAT3 are critical cellular effectors of TRE17 in the pathogenesis of ARMS and ABC/NF. Aim 1: Determine role of Jak1/STAT and NFkB pathways in TRE17- mediated proliferation and survival. TRE17's USP activity is essential for tumorigenesis, and preliminary data implicate Jak1, the STAT3 kinase, as its first substrate. Exciting new results show that Jak1 can be modified by ubiquitin and the Ub-like molecule, ISG15, and suggest TRE17 may counteract both of these modifications to induce its stabilization. Cell culture-based studies will be used to test this, and to determine whether Jak1/STAT3 and NFkB are essential for TRE17-mediated proliferation, survival, and induction of modulators of the tumor microenvironment. Aim 2: Determine requirement for Jak1/STAT and NFkB in TRE17-mediated tumorigenesis in murine models of ABC/NF. We have developed murine xenograft models of ABC and NF, tumors driven by TRE17 translocation. We will examine whether NFkB/Jak1/STAT3 are required cell- autonomous requirement for tumor cell survival and proliferation, and determine their role in modulating the inflammatory and angiogenic microenvironment using immunohistochemistry and in vivo bioluminescence imaging. Aim 3: Determine role of TRE17 and NFkB/STAT3 in ARMS pathogenesis. ARMS is a highly malignant BSTT with dismal survival rates. Through analysis of patient-derived ARMS cell lines and primary tumor samples, we will determine whether TRE17 is an essential mediator of ARMS pathogenesis, and whether it functions through Jak1/STAT3 and NFkB. We will examine the requirement of these factors in growth and proliferation in vitro, including their role within ARMS cancer stem cells. Transcriptome analysis will be performed to define a TRE17-response signature. Finally, we will determine the roles of TRE17, Jak1/STAT3 and NFkB in ARMS tumor formation, maintenance, and metastasis in mice. These studies may ultimately lead to novel approaches (TRE17-specific USP inhibitors, and NFkB and Jak1/STAT inhibitors) for the treatment of lethal cancers such as ARMS, and other BSTTs in which TRE17 is overexpressed.

描述（由申请人提供）：骨和软组织肿瘤（BSTT）是人类肿瘤学中重要但研究不足的实体。由于对其发病机制的认识不全面，限制了有效治疗方法的发展。该建议的重点是TRE 17/泛素特异性蛋白酶6（USP 6）在BSTT发病机制中的作用。TRE 17的复发性易位发生在两种BSTT，囊性骨囊肿（ABC）和结节性筋膜炎（NF）中，导致野生型TRE 17的过表达。TRE 17过表达也选择性地出现在其他BSTT中，特别是高致死性腺泡状横纹肌肉瘤（ARMS）。TRE 17以依赖于其USP活性的方式有效地激活转录因子NFkB和STAT 3。NFkB和STAT 3在癌症中经常失调，通常协调地促进肿瘤细胞存活和增殖、炎症和血管生成。该提案将测试NFkB和STAT 3是否是ARMS和ABC/NF发病机制中TRE 17的关键细胞效应物。目的1：确定Jak 1/STAT和NFkB通路在TRE 17介导的增殖和存活中的作用。TRE 17的USP活性对于肿瘤发生是必不可少的，并且初步数据暗示STAT 3激酶Jak 1是其第一底物。令人兴奋的新结果表明，Jak 1可以被泛素和Ub样分子ISG 15修饰，并表明TRE 17可以抵消这两种修饰以诱导其稳定。细胞培养研究将 用于测试这一点，并确定Jak 1/STAT 3和NFkB是否是TRE 17介导的增殖，存活和诱导肿瘤微环境调节剂所必需的。目的2：确定ABC/NF小鼠模型中TRE 17介导的肿瘤发生对Jak 1/STAT和NFkB的需求。我们已经开发了ABC和NF的小鼠异种移植模型，肿瘤由TRE 17易位驱动。我们将研究NFkB/Jak 1/STAT 3是否是肿瘤细胞存活和增殖所必需的细胞自主性要求，并使用免疫组织化学和体内生物发光成像来确定它们在调节炎症和血管生成微环境中的作用。目的3：确定TRE 17和NFkB/STAT 3在ARMS发病机制中的作用。ARMS是一种高度恶性的BSTT，生存率低。通过分析患者来源的ARMS细胞系和原发性肿瘤样本，我们将确定TRE 17是否是ARMS发病机制的重要介质，以及它是否通过Jak 1/STAT 3和NF κ B发挥作用。我们将研究这些因子在体外生长和增殖中的需求，包括它们在ARMS癌症干细胞中的作用。将进行转录组分析以定义TRE 17应答特征。最后，我们将确定TRE 17，Jak 1/STAT 3和NFkB在小鼠ARMS肿瘤形成，维持和转移中的作用。这些研究可能最终导致新的方法（TRE 17特异性USP抑制剂，以及NFkB和Jak 1/STAT抑制剂）用于治疗致命癌症，如ARMS和TRE 17过表达的其他BSTT。