Pathogenic Roles of SHP2 & PTPRD Tyrosine Phosphatases in High-Risk Neuroblastoma

SHP2 的致病作用

• 批准号: 8725499
• 负责人: Shizhen Zhu
• 金额: $ 12.27万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725499
• 关键词: Accounting; Animals; Apoptotic; Award; Biology; Breast; Cancer Biology; Cell Line; Cell Survival; Cessation of life; Child; Childhood; China; Chronic; Communities; Coupled; DNA; DNA Resequencing; Dana-Farber Cancer Institute; Development; Disease; Doxycycline; Embryo; Environment; GAB2 gene; Genes; Genomics; Goals; Health; Human; Institution; Investigation; Laboratory Finding; Lead; Life; MYCN gene; Maintenance; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediator of activation protein; Medical; Mentors; Mentorship; Modeling; Molecular; Molecular Target; Mutation; Myelogenous; NTRK1 gene; Neuroblastoma; Non-Receptor Type 11 Protein Tyrosine Phosphatase; Normal tissue morphology; Oncogenes; PTPN11 gene; Pathogenesis; Pathologic; Pathway interactions; Pediatric Oncology; Peripheral; Phase; Phosphoric Monoester Hydrolases; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Qualifying; RNA; Research; Research Personnel; Risk; Role; Signal Transduction; Signaling Molecule; Singapore; Structure; Sympathetic Nervous System; System; Testing; Time; Tissues; Toxic effect; Training; Transgenic Organisms; Treatment Failure; Tumor Suppressor Genes; Tumor Suppressor Proteins; Variant; Work; Zebrafish; cancer cell; chemotherapy; high risk; improved; in vivo Model; inhibitor/antagonist; instructor; member; microdeletion; neoplastic cell; neuroblastoma cell; next generation; novel; overexpression; research study; response; small molecule; success; tumor

DESCRIPTION (provided by applicant): Neuroblastoma, a highly malignant tumor that arises in the peripheral sympathetic nervous system, accounts for ~10% of all cancer-related deaths in children. Recent genomic resequencing of high-risk neuroblastoma has uncovered three main classes of mutations: those activating the ALK tyrosine kinase (8- 10% of cases), those activating the SHP2 phosphatase (2-3%), and microdeletions involving the PTPRD locus (6-10%). I recently demonstrated that activated ALK synergizes with MYCN to induce neuroblastoma in zebrafish by inhibiting a developmentally-timed apoptotic response (Zhu et al, Cancer Cell). I have now discovered that activated SHP2 or Ptprd loss also accelerates MYCN-induced neuroblastoma, but in a different way than does activated ALK. On the advice of my close collaborator, Dr. Ben Neel, an internationally recognized expert on phosphatase biology, I have determined that multiple components of the SHP2 pathway are highly overexpressed in most human neuroblastomas, including GAB2, a known oncogene and SHP2 regulator, as well as ALK and NTRK1. The central hypothesis to be explored here is that SHP2 and PTPRD represent vital pathways to the development of neuroblastoma and warrant further intensive investigation. My key objective is to elucidate the underlying mechanisms by which these two pathways influence neuroblastoma initiation and maintenance. My specific aims are (1) to define the mechanisms by which mutationally activated SHP2 contributes to neuroblastoma initiation and maintenance, and determine whether the SHP2 pathway is aberrantly activated in neuroblastoma cases that lack SHP2 mutations; and (2) to elucidate the mechanisms by which loss of the PTPRD tumor suppressor gene contributes to neuroblastoma initiation and maintenance. In these two Aims, I will use mosaic and stable transgenic as well as structure- function approaches to implicate key downstream pathways and a novel tissue-specific, conditional doxycycline-regulated system to establish whether activated SHP2 or loss of PTPRD is continuously required for tumor cell survival, thus qualifying as "drivers" of neuroblastoma pathogenesis. Dr. Shizhen (Jane) Zhu is an instructor in the Department of Pediatric Oncology at the Dana-Farber Cancer Institute (DFCI) working under the mentorship of Dr. A. Thomas Look, a pioneer in the field of zebrafish cancer biology. Building on Dr. Zhu's medical and scientific training in China and Singapore, she is now defining the roles of aberrant SHP2 and PTPRD tyrosine phosphatase pathways in the neuroblastoma pathogenesis. Dr. Look's proven mentorship coupled with the rigorous and nurturing scientific environment offered by the research community at DFCI and affiliated institutions offer the maximal opportunity for Dr. Zhu's success during her award period as an instructor and in her transition to become an independent investigator.

描述（由申请人提供）：神经母细胞瘤是一种发生于周围交感神经系统的高度恶性肿瘤，约占所有儿童癌症相关死亡的 10%。最近对高危神经母细胞瘤的基因组重测序发现了三类主要突变：激活 ALK 酪氨酸激酶的突变（8-10% 的病例）、激活 SHP2 磷酸酶的突变（2-3%）以及涉及 PTPRD 位点的微缺失（6-10%）。我最近证明，激活的 ALK 与 MYCN 协同作用，通过抑制发育定时的细胞凋亡反应来诱导斑马鱼神经母细胞瘤（Zhu 等人，Cancer Cell）。我现在发现激活的 SHP2 或 Ptprd 丢失也会加速 MYCN 诱导的神经母细胞瘤，但方式与激活的 ALK 不同。根据我的密切合作者、国际公认的磷酸酶生物学专家 Ben Neel 博士的建议，我确定 SHP2 通路的多个成分在大多数人类神经母细胞瘤中高度过度表达，包括 GAB2（一种已知的癌基因和 SHP2 调节因子）以及 ALK 和 NTRK1。这里要探讨的中心假设是 SHP2 和 PTPRD 代表神经母细胞瘤发展的重要途径，值得进一步深入研究。我的主要目标是阐明这两种途径影响神经母细胞瘤发生和维持的潜在机制。我的具体目标是（1）定义突变激活的SHP2促进神经母细胞瘤发生和维持的机制，并确定在缺乏SHP2突变的神经母细胞瘤病例中SHP2通路是否异常激活； (2) 阐明 PTPRD 肿瘤抑制基因的缺失导致神经母细胞瘤发生和维持的机制。在这两个目标中，我将使用嵌合和稳定转基因以及结构功能方法来暗示关键的下游途径，并使用一种新颖的组织特异性、条件性多西环素调节系统来确定肿瘤细胞存活是否持续需要激活的SHP2或PTPRD的丢失，从而有资格成为神经母细胞瘤发病机制的“驱动因素”。 Shizhen (Jane) Zhu 博士是丹纳法伯癌症研究所 (DFCI) 儿科肿瘤科的讲师，在斑马鱼癌症生物学领域的先驱 A. Thomas Look 博士的指导下工作。基于朱博士在中国和新加坡接受的医学和科学培训，她现在正在确定异常的 SHP2 和 PTPRD 酪氨酸磷酸酶途径在神经母细胞瘤发病机制中的作用。 Look 博士经过验证的指导，加上 DFCI 及其附属机构的研究界提供的严谨和培育的科学环境，为朱博士在作为讲师的获奖期间以及向独立研究者的过渡期间取得成功提供了最大的机会。