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）：骨和软组织肿瘤（BSTTs）是人类肿瘤学中重要但尚未被充分研究的实体。我们对其发病机制的不完全了解限制了有效治疗的发展。本文主要研究TRE17/泛素特异性蛋白酶6 （USP6）在BSTT发病机制中的作用。TRE17的反复易位发生在动脉瘤性骨囊肿（ABC）和结节性筋膜炎（NF）两种bstt中，导致野生型TRE17过表达。TRE17过表达也选择性地出现在其他bstt中，特别是高致死性肺泡横纹肌肉瘤（ARMS）。TRE17有效激活转录因子NFkB和STAT3，其激活方式取决于其USP活性。NFkB和STAT3在癌症中经常失调，通常是协调的，以促进肿瘤细胞的存活和增殖、炎症和血管生成。本研究将检验NFkB和STAT3是否为TRE17在ARMS和ABC/NF发病机制中的关键细胞效应因子。目的1：确定Jak1/STAT和NFkB通路在TRE17介导的增殖和存活中的作用。TRE17的USP活性对肿瘤发生至关重要，初步数据表明STAT3激酶Jak1是其第一个底物。令人兴奋的新结果表明，Jak1可以被泛素和ub样分子ISG15修饰，并提示TRE17可能抵消这两种修饰以诱导其稳定。基于细胞培养的研究将会