Integrative genomic characterization of lung cancer metastasis in mouse and human

小鼠和人类肺癌转移的综合基因组特征

• 批准号: 7924626
• 负责人: TYLER E. JACKS
• 金额: $ 79.07万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924626
• 关键词: Behavior; Bioinformatics; Biological; Biological Process; Blood; Cancer Patient; Candidate Disease Gene; Cells; DNA Sequence; Data; Diagnosis; Disease; Epigenetic Process; Frequencies; Gene Expression; Genes; Genetic; Genetic Screening; Genetically Engineered Mouse; Genomics; Health; Human; Individual; K-ras Oncogene; Lead; Left; Link; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metastatic Lesion; Metastatic to; Methods; Modeling; Molecular; Molecular Genetics; Mus; Mutagenesis; Mutate; Mutation; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Organ; Pathway interactions; Phase; Primary Neoplasm; Process; Protein p53; Sampling; Series; Site; Specimen; System; Technology; Tumor Suppressor Genes; United States; attributable mortality; base; gene function; genetic analysis; human data; improved; in vivo; insight; mouse model; neoplastic cell; next generation; tumor

DESCRIPTION (provided by applicant): Most cancer deaths are attributable to the metastatic phase of the disease. However, the molecular and cellular mechanisms that allow tumor cells to leave the primary site, survive during transit through the blood and establish and maintain a new tumor in a secondary organ remain poorly understood. Using a genetically engineered mouse model of metastatic non-small cell lung cancer in which primary tumors can be unambiguously linked to their metastases, we will systematically and comprehensively characterize alterations at the genetic, gene expression, and epigenetic levels. The model utilizes conditional mutations in the K-Ras oncogene and the p53 tumor suppressor gene, which are both mutated at high frequency in human lung cancer. These studies will employ cutting-edge methods in molecular genetic analysis, relying extensively on next generation DNA sequencing technology. In addition, we will use transposon-mediated mutagenesis system to perform a forward genetic screen to identify genes that enhance metastatic behavior. Data from these studies will be subjected to integrative bioinformatic analysis to increase the ability to identify metastasis pathways, including performing cross-species analysis with data from human lung cancer specimens. Candidate genes and pathways will be validated in large series of tumors and metastases from the mouse model as well as in human lung cancer patient samples. We will probe the biological function of candidate metastasis genes and pathways using a combination of cell-based and in vivo approaches, including altering gene function in the autochthonous model. The information gained from these studies is expected to provide new insights into the biological basis of metastasis in mouse models and in human lung cancer. An improved understanding of these processes has the potential to improve diagnosis of aggressive lung cancer, lead to treatments that target metastatic lesions as well as methods to inhibit metastatic spread. Given that an estimated 1.4 million individuals will succumb to lung cancer in the United States and throughout the world over the next year, most of them from the consequences of metastasis, new insights into lung cancer metastasis are highly relevant to human health.

描述（由申请人提供）：大多数癌症死亡归因于该疾病的转移阶段。然而，允许肿瘤细胞离开主要部位的分子和细胞机制，在通过血液过渡过程中生存，并在次级器官中建立和维持新的肿瘤仍然知之甚少。使用转移性非小细胞肺癌的基因工程小鼠模型，其中原发性肿瘤可以与其转移酶明确联系起来，我们将系统地和全面地表征遗传，基因表达和表观遗传水平的变化。该模型利用K-RAS癌基因和p53肿瘤抑制基因中的条件突变，它们在人类肺癌中都在高频中突变。这些研究将在分子遗传分析中采用尖端方法，并广泛依赖于下一代DNA测序技术。此外，我们将使用转座子介导的诱变系统执行正向遗传筛选，以识别增强转移行为的基因。这些研究的数据将经过综合生物信息学分析，以提高鉴定转移途径的能力，包括对人类肺癌标本的数据进行跨物种分析。候选基因和途径将在小鼠模型以及人类肺癌患者样本中的大量肿瘤和转移中进行验证。我们将使用基于细胞和体内方法的组合探测候选转移基因和途径的生物学功能，包括在自节体模型中改变基因功能。从这些研究中获得的信息预计将为小鼠模型和人肺癌中转移的生物学基础提供新的见解。对这些过程的提高了解有可能改善侵袭性肺癌的诊断，导致靶向转移性病变的治疗方法以及抑制转移性扩散的方法。鉴于估计有140万人将屈服于美国乃至全球的肺癌，因此大多数人来自转移的后果，对肺癌转移的新见解与人类健康高度相关。