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（BSTT）是人类肿瘤学中重要但尚未得到充分研究的实体。我们对其发病机制的不完全了解限制了有效疗法的开发。该提案重点关注 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：动脉瘤性骨囊肿 (ABC) 和结节性筋膜炎 (NF)，导致野生型 TRE17 过度表达。 TRE17 过表达也在其他 BSTT 中选择性出现，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，其方式取决于其 USP 活性。 NFkB 和 STAT3 在癌症中经常失调，通常协同作用，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 STAT3 是否是 TRE17 在 ARMS 和 ABC/NF 发病机制中的关键细胞效应子。目标 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 活性对于肿瘤发生至关重要，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，并表明 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 用于测试这一点，并确定 Jak1/STAT3 和 NFkB 是否对于 TRE17 介导的增殖、存活和肿瘤微环境调节剂的诱导至关重要。目标 2：确定 ABC/NF 小鼠模型中 TRE17 介导的肿瘤发生对 Jak1/STAT 和 NFkB 的需求。我们开发了 ABC 和 NF 的小鼠异种移植模型，这是由 TRE17 易位驱动的肿瘤。我们将检查 NFkB/Jak1/STAT3 是否是肿瘤细胞生存和增殖所必需的细胞自主要求，并使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。目标 3：确定 TRE17 和 NFkB/STAT3 在 ARMS 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 ARMS 细胞系和原发肿瘤样本的分析，我们将确定 TRE17 是否是 ARMS 发病机制的重要介质，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 ARMS 癌症干细胞中的作用。将进行转录组分析来定义 TRE17 响应特征。最后，我们将确定 TRE17、Jak1/STAT3 和 NFkB 在小鼠 ARMS 肿瘤形成、维持和转移中的作用。这些研究可能最终会带来新的方法（TRE17特异性USP抑制剂，以及NFkB和Jak1/STAT抑制剂），用于治疗致死性癌症，例如ARMS和其他TRE17过表达的BSTT。