Mechanisms of PPM1D in medulloblastoma tumorigenesis and invasion

描述（由申请人提供）：PPM 1D（WIP 1）基因在超过50%的髓母细胞瘤和最近描述的4种髓母细胞瘤分子亚群中的3种中过表达。我们的初步数据显示，WIP1过表达也与肿瘤转移和不良的无进展生存率和总生存率相关。本申请的长期目标是确定肿瘤进展和转移的机制和预测因子，以开发改善WIP1过表达髓母细胞瘤患者生存的疗法。我们发现WIP1过表达的髓母细胞瘤与Sonic Hedgehog（SHH）信号传导和趋化因子G蛋白偶联受体CXCR4表现出独特的交叉作用，而这种交叉作用的特征并不明显。我们的中心假设是，WIP1过表达改变SHH信号级联的表达或激活的组件，并导致CXCR4的异常定位或激活，导致WIP1过表达的髓母细胞瘤细胞的生长，侵袭和转移增加。采用创新的多学科方法，结合遗传学和药理学，我们将确定（1）MB肿瘤发生中SHH和WIP 1信号传导之间的相互作用机制，（2）WIP 1介导的MB侵袭机制，以及（3）在髓母细胞瘤小鼠模型中靶向WIP 1沿着靶向SHH和CXCR 4信号传导的药物，以改善侵袭性髓母细胞瘤的治疗效果。获得WIP1过表达的多种模型和多种人髓母细胞瘤组织集使我们处于发现新的治疗靶点的独特位置。最终，这项研究将通过在WIP1过表达的髓母细胞瘤中确定新的分子靶点和新的药物组合来造福人类健康。了解与WIP1过表达相关的分子机制将最终导致改善，毒性更小的治疗策略和提高被诊断患有脑癌的儿童的生存率。

DESCRIPTION (provided by applicant): The PPM1D (WIP1) gene is overexpressed in over 50% of medulloblastomas and in 3 of the 4 recently described medulloblastoma molecular subgroups. Our preliminary data shows that WIP1 overexpression is also associated with tumor metastasis and poor progression-free and overall survival. The long-term goal of this application is to identify mechanisms and predictors of tumor progression and metastasis in order to develop therapies that will improve the survival of patients with WIP1-overexpressing medulloblastoma. We have found that WIP1 overexpressing medulloblastomas exhibit a unique cross-talk with Sonic Hedgehog (SHH) signaling and the chemokine G-protein-coupled receptor CXCR4 that is poorly characterized. Our central hypothesis is that WIP1 overexpression alters expression or activation of components of the SHH signaling cascade and results in aberrant localization or activation of CXCR4, causing increased growth, invasion, and metastasis of WIP1-overexpressing medulloblastoma cells. Using an innovative multidisciplinary approach that combines genetics and pharmacology, we will determine (1) the mechanisms of cross-talk between SHH and WIP1 signaling in MB tumorigenesis, (2) the mechanisms of MB invasion mediated by WIP1, and (3) the efficacy of targeting WIP1 along with agents that target SHH and CXCR4 signaling in mouse models of medulloblastoma to improve the treatment of aggressive medulloblastomas. Access to multiple models of WIP1 overexpression and multiple human medulloblastoma tissue sets places us in a unique position to discover novel therapeutic targets. Ultimately, this study will benefit human health by identifying new molecular targets and novel drug combinations in WIP1-overexpressing medulloblastomas. Understanding the molecular mechanisms associated with WIP1 overexpression will ultimately lead to improved, less toxic therapeutic strategies and improved survival rates in children diagnosed with brain cancer.