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

SHP2 的致病作用

基本信息

批准号：
9329399
负责人：
Shizhen Zhu
金额：
$ 24.9万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9329399
关键词：
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 Human Institution International Investigation Laboratory Finding Lead MYCN gene Maintenance Malignant Neoplasms Mediator of activation protein Medical Mentors Mentorship Modeling Molecular Abnormality Molecular Target Mosaicism Mutation Myelogenous NTRK1 gene Neuroblastoma Normal tissue morphology Oncogenes PTPN11 gene Pathogenesis Pathogenicity 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 Tissues Toxic effect Training Transgenic Organisms Treatment Failure Tumor Suppressor Genes Tumor Suppressor Proteins Variant Work Zebrafish cancer cell chemotherapy childhood cancer mortality experimental study high risk improved in vivo Model instructor member microdeletion neoplastic cell neuroblastoma cell next generation novel overexpression pediatric department public health relevance response small molecule inhibitor success targeted treatment tumor

项目摘要

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高度恶性的肿瘤，是在周围交感神经系统中产生的，占儿童与癌症相关的所有死亡的约10％。高风险神经细胞瘤的最新基因组重新等式发现了三个主要类别的突变类别：激活ALK酪氨酸激酶的突变（占病例的8-10％），那些激活SHP2磷酸酶（2-3％）和涉及涉及PTPRD轨迹的微缺失的突变（6-10％）。我最近证明，激活的ALK与MYCN协同，通过抑制发育定时的凋亡反应来诱导斑马鱼中的神经母细胞瘤（Zhu等人，癌细胞）。我现在发现激活的SHP2或PTPRD损失也加速了MYCN诱导的神经母细胞瘤，但与激活的ALK不同。在我的亲密合作者的建议下，国际认可的磷酸酶生物学专家本·尼尔（Ben Neel）博士确定，在大多数人类神经母细胞瘤中，SHP2途径的多个组成部分都高度表达，包括GAB2，包括已知的Oncogene和SHP2调节剂，以及Alk和Ntrk1。这里要探讨的中心假设是SHP2和PTPRD代表了神经母细胞瘤发展的重要途径，并保证了进一步的深入研究。我的主要目的是阐明这两种途径影响神经母细胞瘤开始和维持的潜在机制。我的具体目的是（1）定义突变激活的SHP2有助于神经母细胞瘤的起始和维持的机制，并确定在缺乏SHP2突变的神经母细胞瘤病例中SHP2途径是否被异常激活；（2）阐明了PTPRD抑制基因丧失的机制，有助于神经母细胞瘤的起始和维持。在这两个目标中，我将使用马赛克和稳定的转基因以及结构功能方法，暗示关键的下游途径和一种新型的组织特异性，条件性的多西环素调节系统来确定激活的SHP2或PTPRD的损失是否是tumor细胞的持续所必需的。 Shizhen（Jane）Zhu博士是Dana-Farber癌症研究所（DFCI）的儿科肿瘤学系的讲师。在朱博士在中国和新加坡的医学和科学培训的基础上，她现在定义了异常SHP2和PTPRD酪氨酸磷酸酶途径在神经母细胞瘤发病机理中的作用。 Look博士的经验丰富的指导，加上DFCI研究界和附属机构提供的严格而培养的科学环境，为朱博士在奖励期间获得教练的成功和成为独立研究员的过渡期间为Zhu博士的成功提供了最大的机会。