Systems genetics analysis of tumor evolution in the mouse

小鼠肿瘤进化的系统遗传学分析

• 批准号: 10621723
• 负责人: ALLAN BALMAIN
• 金额: $ 93.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621723
• 关键词: Animals; Benign; Biological Markers; Biological Models; Cancer Model; Cancer-Predisposing Gene; Cause of Death; Cells; Chemicals; Complex; Databases; Distant Metastasis; Environment; Environmental Exposure; Evolution; Exposure to; Frequencies; Funding; Genes; Genetic; Genetic Determinism; Genomics; Genotype; Goals; Head and neck structure; Human; Immune checkpoint inhibitor; Immunotherapy; Inherited; Lesion; Lung; Malignant - descriptor; Malignant Neoplasms; Modeling; Mouse Strains; Mus; Mutagens; Mutation; Neoplasm Metastasis; Outcome; Pathway Analysis; Pathway interactions; Population; Primary Carcinoma; Proteins; Radiation; Research; Risk; Route; Sampling; Series; Signal Pathway; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; System; Technology; Testing; Tissue Banks; Tumor Bank; Tumor Promotion; carcinogenesis; carcinogenicity; cohort; genetic analysis; genome-wide; genomic profiles; human model; individual patient; mouse model; mutant; neoantigens; novel; novel therapeutics; response; tool; translational study; tumor; tumor DNA; Animals; Benign; Biological Markers; Biological Models; Cancer Model; Cancer-Predisposing Gene; Cause of Death; Cells; Chemicals; Complex; Databases; Distant Metastasis; Environment; Environmental Exposure; Evolution; Exposure to; Frequencies; Funding; Genes; Genetic; Genetic Determinism; Genomics; Genotype; Goals; Head and neck structure; Human; Immune checkpoint inhibitor; Immunotherapy; Inherited; Lesion; Lung; Malignant - descriptor; Malignant Neoplasms; Modeling; Mouse Strains; Mus; Mutagens; Mutation; Neoplasm Metastasis; Outcome; Pathway Analysis; Pathway interactions; Population; Primary Carcinoma; Proteins; Radiation; Research; Risk; Route; Sampling; Series; Signal Pathway; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; System; Technology; Testing; Tissue Banks; Tumor Bank; Tumor Promotion; carcinogenesis; carcinogenicity; cohort; genetic analysis; genome-wide; genomic profiles; human model; individual patient; mouse model; mutant; neoantigens; novel; novel therapeutics; response; tool; translational study; tumor; tumor DNA

Abstract Systems Genetics Analysis of Tumor Evolution in the Mouse. Metastasis is the major cause of death due to cancer in humans, but many factors play a role in determining the route taken by initiated cells to reach this end stage. We know that tumors arise due to the combined effects of inherited genetic factors and environmental exposures, and have taken the long term view that successful modeling of human cancer in the mouse requires us to take account of interactions between genetics and environment. The over-arching goal of this research is to develop an integrated systems genetics view of the cells, signaling pathways and mutations in specific genes involved in evolution of metastasis from single initiated cells, using one of the best characterized models of multistage carcinogenesis of the skin. Based on major funding from the NCI MMHCC over the past 15 years, we have built up a unique tissue and tumor bank comprising thousands of samples of Ras-mutant squamous tumors from a genetically heterogeneous mouse population. These samples encompass all stages from benign lesions to metastases, and in particular include hundreds of matched primary carcinomas and distant metastases from the same animals. All tumors were induced by exposure to mutagens and tumor promoting agents, resulting in complex genomic landscapes that resemble, in mutation frequency and type, the genomic profiles of human squamous carcinomas of the skin, head and neck, and lung. All mice in the cohort have been genotyped genome-wide to facilitate linkage and eQTL analysis to identify genetic determinants of initiation, benign tumor formation, progression and metastatic dissemination. This project will exploit this unique tissue bank and database by using genomic technologies, together with novel mouse strains, to identify the cells of origin of benign and malignant tumors, biomarkers of risk of malignant progression, and genetic drivers of metastasis. Computational network analysis tools will be used to study the evolution of signaling pathways, for example the Ras pathway, through multiple stages of carcinogenesis, to identify changes in these networks that will identify potential novel cancer target genes. Finally we will initiate a new series of translational studies of immunotherapy, based on our observation that these chemically induced tumors harbor novel neo-antigens and show promising responses to inhibitors of immune checkpoint proteins.

抽象的 小鼠肿瘤进化的系统遗传学分析。 转移是人类癌症引起的主要死亡原因，但许多因素在确定中起作用 启动细胞采取的途径到达该末端阶段。我们知道肿瘤是由于总和 继承的遗传因素和环境暴露的影响，并采取了长期观点 在小鼠中成功建模人类癌症需要我们考虑 遗传学和环境。这项研究的整理目标是开发集成的系统遗传学 细胞的视图，信号通路和突变的特定基因中涉及转移进化的特定基因 单个启动细胞，使用皮肤多阶段癌变的最佳特征模型之一。 基于过去15年中NCI MMHCC的主要资金，我们建立了独特的组织和 肿瘤库包括数千种来自遗传学的Ras突变剂鳞状肿瘤 异质小鼠种群。这些样品包括从良性病变到转移酶的所有阶段， 特别是包括数百种匹配的原发性癌和远处转移 动物。暴露于诱变剂和肿瘤促进剂，使所有肿瘤诱导，从而导致复杂 类似于突变频率和类型的基因组景观，是人类鳞状的基因组谱 皮肤，头部和颈部和肺的癌。队列中的所有小鼠均被基因组全基因组至 促进连锁和EQTL分析以确定起始，良性肿瘤形成的遗传决定因素， 进展和转移传播。该项目将通过 使用基因组技术以及新型小鼠菌株，以识别良性和 恶性肿瘤，恶性进展风险的生物标志物以及转移的遗传驱动因素。 计算网络分析工具将用于研究信号通路的演变，例如 RAS途径通过癌变的多个阶段，以识别这些网络中的变化，以识别 潜在的新型癌症靶基因。最后，我们将启动一系列新的翻译研究 免疫疗法，基于我们的观察，这些化学诱导的肿瘤具有新的新抗原 并显示出对免疫检查点蛋白抑制剂的有希望的反应。