Tumor maintenance and development in mouse models

描述(由申请人提供)： 参与这项计划的四个实验室将制造和使用几个人类癌症模型，以寻求至少三个问题，这些问题启发了目前在小鼠模型中的工作--维持(定义维持活的肿瘤表型所需的功能)、命运决定(探索发育谱系的细胞成分和被突变的癌症基因转化的细胞表型之间的关系)和再生(测试负责肿瘤持续生长和复发的细胞的存在和特征，即“癌症干细胞”)。具体目标包括：(I)通过设计和分析影响肺、卵巢和胰腺上皮、成纤维细胞和造血细胞(B细胞和髓系细胞系)的人类癌症的多步骤模型，识别维持恶性肿瘤基本特征所需的遗传损伤；(Ii)表征发育谱系中的细胞与在该谱系中产生不同表型肿瘤的致癌事件之间的相互作用，重点是胰腺、乳腺和造血系统肿瘤；(Iii)识别这些肿瘤中负责驱动肿瘤生长从而在治疗后补充肿瘤的细胞；以及(Iv)继续改进几个现有的模型(例如，针对肺癌、胰腺癌和乳腺癌)，并启动新的模型(针对纤维肉瘤、多发性骨髓瘤和早幼粒细胞白血病)，以促进追求AIMS(I)、(Ii)和(Iii)。我们将使用传统方法对小鼠生殖系进行遗传改变(转基因和靶向突变)，以及其他基因调控、组织和细胞类型特异性效应和体细胞基因传递的方法(例如，利用禽流感病毒载体、四环素反应调节因子和抑制RNA)。

DESCRIPTION (provided by applicant): The four laboratories participating in this program will produce and use several models of human cancer to pursue at least three problems that inspire current work with mouse models -- maintenance (defining the functions required to maintain a viable tumor phenotype), fate determination (exploring the relationship between cellular components of a developmental lineage and the phenotypes of cells transformed by mutant cancer genes), and regeneration (testing for the existence and characteristics of cells responsible for sustained growth and recurrence of tumors, "cancer stem cells"). Specific aims include: (i) To identify genetic lesions required for maintenance of the essential features of malignancy, through the design and analysis of multi-step models of human cancer, affecting lung, ovarian, and pancreatic epithelium, fibroblasts, and hematopoietic cells (B cell and myeloid cell lineages); (ii) To characterize the interaction between cells in a developmental lineage and the oncogenic events that produce tumors of different phenotypes in that lineage, with emphasis on pancreatic, breast, and hematopoietic tumors; (iii) To identify cells within such tumors that are responsible for driving tumor growth and thus replenishing tumors after therapy; and (iv) To continue to refine several existing models (e.g. for lung, pancreatic, and breast carcinomas) and initiate new models (for fibrosarcoma, multiple myeloma, and promyelocytic leukemia) that facilitate the pursuit of aims (i), (ii), and (iii). We will employ traditional means for genetic alteration of the mouse germ line (transgenes and targeted mutations), as well as other methods for gene regulation, tissue- and cell type-specific effects and somatic cell gene delivery (e.g. with avian virus vectors, tetracycline-responsive regulators and inhibitory RNAs).