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(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。我们对其发病机制的不完全理解限制了有效治疗方法的发展。这项建议集中在TRE17/泛素特异性蛋白酶6(USP6)在BSTT发病机制中的作用。TRE17的反复易位发生在两种BSTT中，动脉瘤样骨囊肿(ABC)和结节性筋膜炎(NF)，导致野生型TRE17的过度表达。TRE17的过度表达也选择性地出现在其他BSTT中，特别是高度致命性的肺泡型横纹肌肉瘤(ARMS)。TRE17以依赖于其USP活性的方式有效地激活转录因子NFkB和STAT3。NFkB和STAT3在肿瘤中经常处于失调状态，通常是协同作用的，以促进肿瘤细胞的存活和增殖、炎症和血管生成。这项建议将测试NFkB和STAT3是否是TRE17在ARMS和ABC/NF发病机制中的关键细胞效应因子。目的1：探讨JAK1/STAT和NFkB信号通路在TRE17介导的细胞增殖和存活中的作用。TRE17‘S的USP活性在肿瘤的发生中是必不可少的，初步数据表明JAK1，STAT3激酶是其第一底物。令人兴奋的新结果表明，JAK1可以被泛素和类似Ub的分子ISG15修饰，并表明TRE17可能抵消了这两种修饰，从而诱导其稳定。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TRE17介导的增殖、存活和肿瘤微环境调节因子的诱导至关重要。目的2：确定在TRE17介导的ABC/NF小鼠肿瘤发生过程中对JAK1/STAT和NFkB的需求。我们已经建立了由TRE17易位驱动的ABC和NF的小鼠异种移植模型。我们将研究NFkB/JAK1/STAT3是否是肿瘤细胞生存和增殖所必需的细胞自主要求，并利用免疫组织化学和体内生物发光成像确定它们在调节炎症和血管生成微环境中的作用。目的：探讨TRE17和NFkB/STAT3在ARM发病机制中的作用。ARMS是一种高度恶性的BSTT，存活率很低。通过对患者来源的ARM细胞系和原发肿瘤样本的分析，我们将确定TRE17是否是ARM发病机制的重要中介，以及它是否通过JAK1/STAT3和NFkB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，包括它们在武器癌干细胞中的作用。将进行转录组分析以确定TRE17-响应签名。最后，我们将确定TRE17、JAK1/STAT3和NFkB在小鼠上肢肿瘤形成、维持和转移中的作用。这些研究可能最终导致新的方法(TRE17特异性USP抑制剂，以及NFkB和JAK1/STAT抑制剂)用于治疗致命癌症，如ARM和其他TRE17过表达的BSTT。