Transcriptional Regulation of Lung Cancer Identity

肺癌身份的转录调控

• 批准号: 10330897
• 负责人: Eric Lee Snyder
• 金额: $ 1.89万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330897
• 关键词: Cancer Etiology; Cancer cell line; Cells; Cessation of life; Clinical; DNA Sequence Alteration; Differentiation and Growth; Disease; Drug resistance; Exhibits; Genes; Genetic Drift; Genetically Engineered Mouse; Goals; Heterogeneity; Human; Lung Adenocarcinoma; Malignant - descriptor; Malignant neoplasm of lung; Patients; Prognosis; Research; Role; Testing; Therapeutic; Transcriptional Regulation; cancer cell; therapeutic development; transcription factor; tumor

Project Summary Lung adenocarcinoma, the most common cause of cancer death worldwide, exhibits substantial heterogeneity in cellular identity, or differentiation state. In this disease, cancer cell identity correlates with critical clinical parameters, including patient prognosis, intrinsic sensitivity to therapy, and acquisition of drug resistance. Despite these correlations, major unanswered questions remain with respect to a) the regulatory networks controlling lung adenocarcinoma identity and (b) the mechanisms by which perturbation of these networks alters malignant potential. A major rationale for this proposal is that a mechanistic understanding of lineage specification in lung cancer must be achieved before differentiation state-specific therapeutic strategies can be developed. The immediate goal of this application is to test the central hypothesis that the transcription factors NKX2-1/TTF1, FOXA1 and FOXA2 coordinately regulate a gene network that controls lung adenocarcinoma differentiation and growth. This hypothesis will be tested in the following specific aims via an integrative experimental approach that employs genetically engineered mouse (GEM) models, analysis of primary human tumors, and functional studies in human cancer cell lines: (1) Characterize the role of FOXA1 and FOXA2 (FOXA1/2) in NKX2-1-positive lung adenocarcinoma. (2) Determine how global re-localization of FOXA1/2 after NKX2-1 loss impacts lung adenocarcinoma growth and differentiation. (3) Identify mechanisms by which NKX2- 1 represses non-pulmonary cell fates in lung adenocarcinoma.

项目摘要 肺腺癌是世界范围内最常见的癌症死亡原因，表现出很大的异质性。 处于细胞同一性，或分化状态。在这种疾病中，癌细胞的特性与危重的临床相关。 参数，包括患者预后、对治疗的内在敏感性和获得耐药性。 尽管存在这些关联，但关于a)监管网络的主要问题仍然悬而未决 控制肺腺癌的身份和(B)这些网络的扰动改变的机制 可能是恶性的。这一提议的一个主要理由是，对世系的机械性理解 在分化状态特定的治疗策略可以之前，必须达到肺癌的规范 发展起来的。这个应用程序的直接目标是测试转录因子 Nkx2-1/TTF1、FOXA1和FOXA2协同调控控制肺腺癌的基因网络 分化和生长。这一假设将在以下具体目标中进行检验，通过综合 采用基因工程小鼠(GEM)模型的实验方法，分析原始人 人类癌细胞系中的肿瘤和功能研究：(1)表征FOXA1和FOXA2的作用 (FOXA1/2)在NKX2-1阳性肺腺癌中表达。(2)确定FOXA1/2之后的全球重新本地化 Nkx2-1缺失影响肺腺癌的生长和分化。(3)确定NKX2- 1抑制肺腺癌中非肺细胞的命运。