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: 10394264
• 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/10394264
• 关键词: Animals; Benign; 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; Play; Population; Primary Carcinoma; Proteins; Radiation; Research; Risk; Role; Route; Sampling; Series; Signal Pathway; Signal Transduction; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; System; Technology; Testing; Tissue Banks; Tumor Bank; Tumor Markers; base; 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.

摘要 小鼠肿瘤进化的系统遗传学分析。 转移是人类癌症死亡的主要原因，但许多因素在决定因素中起着作用。 被启动的细胞到达这个结束阶段所采取的路线。我们知道肿瘤的产生是由于 遗传遗传因素和环境暴露的影响，并从长远来看 在小鼠中成功地建立人类癌症模型需要我们考虑到 遗传学和环境。这项研究的总体目标是发展一种完整的系统遗传学 肿瘤转移的细胞、信号通路和特定基因突变的研究进展 单一启动细胞，使用皮肤多阶段癌变的最佳特征模型之一。 基于过去15年来自NCI MMHCC的主要资金，我们已经建立了一个独特的组织和 包含数千个RAS突变型鳞癌样本的肿瘤库 不同种类的小鼠。这些样本涵盖了从良性病变到转移的所有阶段， 尤其包括数百例匹配的原发癌和同一来源的远处转移癌 动物。所有肿瘤都是通过暴露于诱变剂和促癌剂而诱发的，从而产生复杂的 在突变频率和类型上与人类鳞状细胞的基因组图谱相似的基因组景观 皮肤癌、头颈部癌和肺癌。队列中的所有小鼠都进行了全基因组的基因分型 促进连锁和eQTL分析以确定启动、良性肿瘤形成、 进展和转移性扩散。该项目将利用这一独特的组织库和数据库，通过 利用基因组技术，结合新的小鼠品系，鉴定良性和非传染性疾病的起源细胞 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。 将使用计算网络分析工具来研究信令路径的演变，例如 RAS途径，通过癌变的多个阶段，识别这些网络中的变化，从而识别 潜在的新的癌症靶向基因。最后，我们将启动一系列新的翻译研究 免疫治疗，基于我们观察到这些化学诱导的肿瘤含有新的新抗原 并对免疫检查点蛋白的抑制剂显示出良好的反应。