Lung cancer initiating cells in a tumor mouse model deficient in Cdkn2ab

缺乏 Cdkn2ab 的肿瘤小鼠模型中的肺癌起始细胞

• 批准号: 8003986
• 负责人: Katja Schuster
• 金额: $ 5.22万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8003986
• 关键词: Cancer Etiology; Cell Polarity; Cells; Cessation of life; Development; Disease; Fluorescence; Genes; Human; Immunofluorescence Immunologic; KRAS2 gene; Label; Lead; Link; Lung; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Mus; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Proteins; Repression; Research; Role; Stem cells; Structure of parenchyma of lung; Tissues; Tumor Suppressor Proteins; United States; Western Blotting; cancer therapy; cell type; in vivo; mouse model; novel; novel therapeutics; public health relevance; reconstitution; self-renewal; stem cell niche; tissue culture; tumor; tumor xenograft; tumorigenesis

DESCRIPTION (provided by applicant): Tumor suppressor pathways are frequently lost in human non-small lung cancers (NSCLC). Their repression furthermore has been linked to the reconstitution of self-renewal potential in fully developed cells and tissue stem cells. The identity of cell type(s) that initiate and maintain lung cancer has remained undefined; and even though a lung stem cell niche exists in the lung; its role in lung cancer tumorigenesis remains indeterminate. The objective of this study is to characterize cancer initiating cells in an oncogene inducible mouse lung tumor model and to elucidate the significance of tumor suppressors from the Cdkn2ab gene locus in lung cancer pathogenesis. We hypothesize that lung tissue stem cells expressing oncogene K-Ras in a Cdkn2ab deficient background will regain their ability to self-renew, lose cell polarity and initiate a malignant more aggressive NSCLC disease as compared to stem cells in the wild-type background. In Aim 1, we will characterize tumor-initiating cells from an oncogene inducible mouse lung tumor model that are genetically labeled with green fluorescence protein (GFP). These cells will be isolated from wild-type and Cdkn2ab deficient backgrounds and characterized in tissue culture using immunofluorescence and western blot analysis. In Aim 2, we will elucidate the effect of loss of tumor suppressors from the Cdkn2ab locus in NSCLC development in vivo by utilizing the oncogenic K-Ras inducible mouse lung tumor and xenograft mouse models. The characterization of cancer-initiating cells in this unique mouse model will provide an ideal platform to classify the molecular networks that determine lung cancer, and further portray these cells as a target for anti-cancer therapies. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer related death in the United States. The proposed research will use a novel lung cancer mouse model in which tumor initiating cells have been genetically labeled for analysis. The characterization of these unique lung cells will provide a platform to elucidate the mechanisms leading to lung cancer and may ultimately lead to the development of lung cancer specific novel therapeutic drugs.

描述（由申请人提供）：肿瘤抑制途径在人类非小肺癌（NSCLC）中经常丢失。 此外，它们的抑制与完全发达的细胞和组织干细胞中的自我更新潜力的重建有关。启动和维持肺癌的细胞类型的身份仍然不确定。即使肺部存在肺部细胞生态位；它在肺癌肿瘤发生中的作用仍然不确定。这项研究的目的是表征在癌基因诱导小鼠肺肿瘤模型中引发细胞的癌症，并阐明CDKN2AB基因基因座中肿瘤抑制子在肺癌发病机理中的重要性。我们假设在CDKN2AB缺陷背景下表达癌基因K-RAS的肺组织干细胞将恢复其自我更新，失去细胞极性并引发与野生型背景中的干细胞相比，具有更具侵略性的NSCLC疾病的能力。 在AIM 1中，我们将表征来自癌基因诱导小鼠肺肿瘤模型的肿瘤发射细胞，该模型用绿色荧光蛋白（GFP）遗传标记。这些细胞将从野生型和CDKN2AB不足的背景中分离出来，并使用免疫荧光和蛋白质印迹分析在组织培养中进行表征。 在AIM 2中，我们将通过利用致癌性K-RAS诱导的小鼠肺肿瘤和异种移植小鼠模型来阐明在体内NSCLC发育中CDKN2AB基因座失去肿瘤抑制子的影响。 在这种独特的小鼠模型中，癌症引发细胞的表征将为确定肺癌的分子网络分类，并进一步将这些细胞描绘成抗癌疗法的靶标。 公共卫生相关性：肺癌是美国与癌症有关的主要原因。拟议的研究将使用一种新型的肺癌小鼠模型，其中肿瘤引发细胞已被遗传标记进行分析。这些独特的肺部细胞的表征将提供一个平台来阐明导致肺癌的机制，并最终可能导致肺癌特异性新型治疗药物的发展。