Cancer and Context

癌症与背景

• 批准号: 9982211
• 负责人: IAN G MACARA
• 金额: $ 93.99万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982211
• 关键词: Breast; Breast Cancer Cell; Breast Epithelial Cells; Cataloging; Catalogs; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Computer Analysis; Coupled; Disease; Environment; Epithelial; Epithelial Cells; Epithelium; Genes; Goals; Human; In Situ; Malignant Neoplasms; Mechanics; Methods; Mitotic spindle; Mus; Mutation; Myoepithelial cell; Neoplasm Metastasis; Oncogenic; Organoids; Phenocopy; Phenotype; Proliferating; Role; Signal Transduction; Site; Stem cell transplant; Structure; System; Technology; Tissues; Tumor Promoters; Tumor Suppression; Tumor Suppressor Proteins; Ursidae Family; anticancer research; cancer cell; cancer initiation; cell behavior; cell transformation; cell type; gene function; malignant breast neoplasm; mammary epithelium; mammary gland development; progenitor; public health relevance; response; tumor initiation; tumorigenesis; tumorigenic

 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（由申请人提供）：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环境的疾病。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耐受，相反，野生型细胞可以在允许的环境中表型复制致瘤细胞。原因尚不完全清楚。然而，一个可能的解释是，上皮细胞中的稳态机制可以抑制肿瘤发生表型。例如，如果正常上皮细胞抑制其邻近细胞的增殖，则转化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编目之外，还迫切需要了解细胞环境如何决定对此类突变的反应。由于大多数人类癌症起源于上皮细胞或其祖细胞，我们的首要目标是确定上皮细胞的稳态机制如何抑制肿瘤发生，重点是乳腺癌。我们认为，转化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起始步骤。细胞如何逃离上皮并在异位部位增殖是理解癌症发生和转移的核心。我们以前的研究，特别是在过去十年中，使我们能够为癌症研究这一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，并开发了一种用于乳腺类器官的人类器官型培养系统，该系统在细胞和组织水平上以非常高的保真度匹配原位结构。这些方法与CRISPR基因编辑技术一起，将用于确定有丝分裂纺锤体错误取向在癌症引发、肌上皮细胞抑制肿瘤以及乳腺癌细胞破坏机械张力信号传导中的作用。我们还与一位实验系统生物学家合作，他将使用全球高内容的信号网络分析与计算分析相结合，以确定对乳腺上皮细胞内稳态机制做出反应的关键节点。我们预测，肿瘤的启动涉及这些节点的组成性激活。总的来说，这项提议带来了多种最先进的方法来解决癌症研究中的一个基本问题，即了解细胞环境如何决定表型。