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Transcriptional Regulation of Lung Cancer Identity

肺癌身份的转录调控

基本信息

批准号：
9382819
负责人：
Eric Lee Snyder
金额：
$ 33.69万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
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/9382819
关键词：
Adopted Alleles Binding Cancer Etiology Cancer cell line Carcinoma Cell Line Cells Cessation of life Chromatin Clinical DNA Sequence Alteration Differentiation and Growth Disease Drug resistance Elements Epigenetic Process Exhibits Gene Activation Gene Expression Genes Genetic Genetic Drift Genetically Engineered Mouse Genome Goals Growth Heterogeneity Histone Acetylation Human Impairment KRAS2 gene Knowledge Lead Lung Lung Adenocarcinoma Lung Neoplasms Malignant - descriptor Malignant neoplasm of lung Microscopic Molecular Mus Mutagenesis Mutation Neoplasms Oncogenic Patients Phenotype Regulator Genes Regulatory Element Research Role Specific qualifier value Squamous Differentiation Stomach System Testing Therapeutic Transcriptional Regulation Work cancer cell design experimental study genetic approach histone methylation human tissue in vivo insight lung tumorigenesis member mouse model mutant outcome forecast pleiotropism programs therapeutic development transcription factor tumor tumor growth

项目摘要

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.

项目总结