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Cancer and Context

癌症与背景

基本信息

批准号：
10221624
负责人：
IAN G MACARA
金额：
$ 94.13万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Although cancer is caused by mutations in tumor suppressor and promoter genes, it is also a disease of cell behavior and cell context. The same mutations that cause transformation in one cell type are often tolerated in others and, conversely, wild type cells can phenocopy tumorigenic cells in a permissive environment. The reasons are not fully understood. However, one likely explanation is that homeostatic mechanisms in epithelia can suppress the tumorigenic phenotype. For example, if normal epithelial cells suppress proliferation of their neighbors, transformed cells might be unable to express their oncogenic potential unless they escape from the epithelial environment. We argue, therefore, that beyond the identification and cataloguing of mutations in human cancers, there is a pressing need to understand how cell context determines the responses to such mutations. Since most human cancers arise from epithelial cells or their progenitors, our over-arching goal is to determine how epithelial homeostatic mechanisms can suppress tumorigenesis, with a focus on breast cancer. We propose that transformed cells need to escape the suppressive signals generated by normal epithelial neighbors and that this is a key initiating step in tumorigenesis. How cells escape the epithelium and proliferate in ectopic sites is central to understanding cancer initiation and metastasis. Our previous studies, particularly over the last decade, have equipped us to make unique contributions to this field of cancer research. We developed a lentiviral transduction/stem cell transplantation method to study gene function in mouse mammary gland development and cancer, and developed a human organotypic culture system for breast organoids that matches in situ structures at the cellular and tissue levels with very high fidelity. These approaches, together with CRISPR gene editing technology, will be used to determine the roles of mitotic spindle mis-orientation in cancer initiation, tumor suppression by myoepithelial cells, and the subversion of mechanical tension signaling by breast cancer cells. We also collaborate with an experimental systems biologist who will use global, high-content analysis of signaling networks coupled with computational analysis, to identify key nodes that respond to homeostatic mechanisms in mammary epithelial cells. We predict that tumor initiation involves the constitutive activation of these nodes. Overal, this proposal brings multiple, state-of-the-art approaches to bear on a fundamental problem in cancer research, to understand how cell context determines phenotype.

描述(申请人提供)：虽然癌症是由肿瘤抑制基因和启动子基因突变引起的，但它也是一种细胞行为和细胞背景的疾病。在一种细胞类型中引起转化的相同突变通常在其他细胞类型中被容忍，相反，野生型细胞可以在允许的环境中表现出致瘤细胞。原因还没有完全弄清楚。然而，一个可能的解释是，上皮细胞中的动态平衡机制可以抑制肿瘤的形成表型。例如，如果正常的上皮细胞抑制其邻近细胞的增殖，转化的细胞可能无法表达其致癌潜力，除非它们逃离上皮环境。因此，我们认为，除了对人类癌症中的突变进行识别和分类之外，迫切需要了解细胞环境如何决定对这些突变的反应。由于大多数人类癌症起源于上皮细胞或其前体细胞，我们的首要目标是确定上皮内环境平衡机制如何抑制肿瘤的发生，重点是乳腺癌。我们认为，转化的细胞需要逃避正常上皮邻居产生的抑制信号，这是肿瘤发生的关键启动步骤。细胞如何逃脱上皮并在异位部位增殖是理解癌症起始和转移的核心。我们之前的研究，特别是过去十年的研究，使我们能够在这一癌症研究领域做出独特的贡献。我们开发了一种慢病毒转导/干细胞移植方法来研究小鼠乳腺发育和癌症中的基因功能，并开发了一种人乳腺器官类物质的器官型培养系统，该系统在细胞和组织水平上与原位结构匹配，并且具有非常高的保真度。这些方法与CRISPR基因编辑技术一起，将被用于确定有丝分裂纺锤体错误定向在癌症启动、肌上皮细胞对肿瘤的抑制以及乳腺癌细胞对机械张力信号的颠覆中的作用。我们还与一位实验系统生物学家合作，他将使用全球高含量的信号网络分析结合计算分析，以确定对乳腺上皮细胞中的动态平衡机制做出反应的关键节点。我们预测，肿瘤的启动涉及这些结节的结构性激活。总体而言，这一建议带来了多种最先进的方法来处理癌症研究中的一个基本问题，以了解细胞环境如何决定表型。