Medulloblastoma and Metastases

描述（由申请人提供）：脑肿瘤是最常见的实体恶性肿瘤，也是儿童癌症相关死亡的主要原因。髓母细胞瘤是儿童最常见的脑肿瘤。MB通过脑脊液播散（转移）到覆盖脑和脊髓的小脑膜。MB的转移难以治疗，基本上定义了无法治愈的肿瘤儿童。我们在Sonic Hedgehog （Shh）信号驱动的MB基因工程小鼠模型中调动了转座因子睡美人（SB），并观察到强劲的转移。匹配的原发性和转移性病变的遗传分析表明，肿瘤经历平行进化，并具有不同的，由转位产生的克隆选择突变。这是第一个能够识别驱动转移基因的小鼠模型。我们假设SB可以揭示克隆组织和进展/转移的基因，这些数据将为人类MB提供信息。我们提出了表征MB患者配对原发性和转移性肿瘤的实验。我们还提出了额外的基于SB的实验，以鉴定新的myn驱动的MB模型中的转移基因，该模型在很大程度上独立于Shh信号，并且可以模拟经典（60%的人类MB）和大细胞。间变性病变（占人类MB的10%）。由于经典的人类MB既可以由myc驱动，也可以由p53缺失驱动，因此我们也将在p53缺失的小鼠中动员SB。3种模型的使用最大限度地减少了由于背景造成的生物效应，表征了MB的广泛遗传亚群，并有助于识别和优先排序：1)。3种不同MB模型中驱动转移的基因。候选转移基因在人MB中发生改变。潜在的治疗靶点。这些数据对治疗具有深远的意义，它假设转移性肿瘤在生物学上与原发肿瘤相似。. 1。从两种匹配的原发性/转移性GEM MB模型中恢复转座子插入位点序列，以确定MB发病机制的重要基因和途径。由信用证。验证SB插入鉴定的候选转移基因的功能重要性。出具。利用人类基因组数据和配对的人MB肿瘤和转移来评估脑轻脑膜弥散的重要层次结构、基因和通路。

DESCRIPTION (provided by applicant): Brain tumors are the most common solid malignancies and the leading cause of cancer- related death in children. Medulloblastoma (MB) is the most common pediatric brain tumor. Dissemination (metastasis) of MB through the cerebrospinal fluid seeds the leptomeningeal membranes that cover the brain and spinal cord. Metastases in MB are refractory to treatment, essentially defining children with incurable tumor. We mobilized the transposable element Sleeping Beauty (SB) in a genetically engineered mouse model of MB driven by Sonic Hedgehog (Shh) signaling and observed robust metastases. Genetic analyses of matched primary and metastatic lesions indicate that tumors undergo parallel evolution and harbor distinct, clonally selected mutations generated by transposition. This is among the first mouse models enabling identification of genes driving metastases. We hypothesize that SB can uncover clonal organization and genes underlying progression/metastasis, and that these data will inform human MB. We propose experiments characterizing paired primary and metastatic tumors from patients with MB. We also propose additional SB based experiments to identify metastases genes in a novel MYCN-driven model for MB which arises largely independently of Shh signaling and which models both classic (60% of human MB) and large cell, anaplastic pathologies (10% of human MB). Because classic human MB can be driven either by myc or by loss of p53, we will also mobilize SB in p53 deficient mice. The use of 3 models minimizes biological effects due to background, characterizes a broad genetic subset of MB, and facilitates identification and prioritization of: 1). Genes driving metastases in 3 distinct models for MB. 2). Candidates metastases genes altered in human MB. 3). Potential therapeutic targets. These data have profound implications for therapy, which assumes that metastases are biologically similar to the primary tumor. A.1.To recover transposon insertion site sequences from matched primary/metastatic GEM MB in two models in order to identify genes and pathways important for MB pathogenesis. A.2.To validate the functional importance of candidate metastases genes identified by SB insertion. A.3.To evaluate hierarchical structures, genes and pathways important for leptomeningeal dispersion using human genomic data, and paired tumors and metastases from human MB. PUBLIC HEALTH RELEVANCE: Medulloblastoma (MB) is a common and frequently lethal tumor of children, for which current therapies are often ineffective. Locoregional dissemination (metastasis) of MB through the cerebrospinal fluid essentially defines incurable MB. Our long term objective is to mobilize the transposable element Sleeping Beauty (SB) in three different genetically engineered mouse models of MB to dissect the clonal organization and genetic bases of malignant progression and leptomeningeal metastasis, to inform human MB. Successful completion of this proposal identifies metastases genes and new therapeutic targets for children with metastatic MB.