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: 9321806
• 负责人: Margaret Mary Chou
• 金额: $ 25.91万
• 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 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321806
• 关键词: Adult; Alpha Cell; 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; Complement; Cytogenetics; Data; Development; Disease; Epithelial; Etiology; Event; Fasciitis; Genetic Engineering; Goals; Growth; Histologic; Human; ISG15 gene; Image; 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; Pathogenicity; Pathologist; Pathway interactions; Patients; Pharmacology; Phosphotransferases; Primary Neoplasm; Recurrence; Rhabdomyosarcoma; Role; STAT3 gene; Sampling; Signal Transduction; Soft Tissue Neoplasms; Survival Rate; Testing; Therapeutic Intervention; USP6 gene; Ubiquitin; Work; Xenograft Model; activating transcription factor; angiogenesis; base; cancer stem cell; cancer type; disabling symptom; effective therapy; experimental study; in vitro Assay; in vivo bioluminescence imaging; inhibitor/antagonist; insight; molecular oncology; mortality; mouse model; neoplastic cell; new therapeutic target; novel strategies; novel therapeutics; oncology; overexpression; paracrine; promoter; public health relevance; response; transcription factor; transcriptome; 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）：骨骼和软组织肿瘤（BSTT）是人类肿瘤学中重要但研究的实体。我们对它们的发病机理的不完全理解有限，对有效疗法的发展有限。该提议着重于TRE17/泛素特异性蛋白酶6（USP6）在BSTT发病机理中的作用。 TRE17的复发易位发生在两个BSTT中，动脉瘤骨囊肿（ABC）和结节性筋膜炎（NF），导致野生型TRE17过表达。 TRE17的过表达也有选择性地在其他BSTT中出现，尤其是高致命的肺泡横纹肌肉瘤（ARM）。 TRE17以取决于其USP活性的方式有效地激活NFKB和STAT3的转录因子。 NFKB和STAT3在癌症（通常是协调）中经常失调，以促进肿瘤细胞的存活和增殖，炎症和血管生成。该建议将测试NFKB和STAT3是否是臂和ABC/NF发病机理中TRE17的关键细胞效应子。目标1：确定JAK1/STAT和NFKB途径在TRE17介导的增殖和存活中的作用。 TRE17的USP活性对于肿瘤发生至关重要，初步数据暗示JAK1（STAT3激酶）是其第一个底物。令人兴奋的新结果表明，JAK1可以通过泛素和类似UB的分子ISG15来改变JAK1，并建议TRE17可以抵消这两种修饰以诱导其稳定。基于细胞培养的研究将 用于测试这一点，并确定JAK1/STAT3和NFKB是否对于TRE17介导的肿瘤微环境调节剂的增殖，存活和诱导是否至关重要。 AIM 2：在ABC/NF的鼠模型中，确定TRE17介导的肿瘤发生中JAK1/STAT和NFKB的需求。我们已经开发了ABC和NF的鼠异种移植模型，这是由TRE17易位驱动的肿瘤。我们将检查NFKB/JAK1/STAT3是否需要对肿瘤细胞存活和增殖的细胞自主需求，并确定它们在使用免疫组织化学和生物生物发光成像调节炎症和血管生成微环境中的作用。 AIM 3：确定TRE17和NFKB/STAT3在手臂发病机理中的作用。武器是一个高度恶性的BSTT，存活率较差。通过分析患者衍生的臂细胞系和原发性肿瘤样品，我们将确定TRE17是否是武器发病机理的必不可少的介体，以及它是否通过JAK1/STAT3和NFKB发挥作用。我们将研究这些因素在体外生长和增殖中的要求，包括它们在臂癌干细胞中的作用。将进行转录组分析以定义TRE17响应签名。最后，我们将在小鼠中确定TRE17，JAK1/STAT3和NFKB在手臂肿瘤形成，维持和转移中的作用。这些研究最终可能导致新的方法（TRE17特异性USP抑制剂，NFKB和JAK1/Stat抑制剂）用于治疗诸如ARM的致命癌和其他TRE17过表达的BSTT。