Characterizing the role of FOXA1 and FOXA2 in NKX2-1 positive lung adenocarcinoma

表征 FOXA1 和 FOXA2 在 NKX2-1 阳性肺腺癌中的作用

• 批准号: 10159071
• 负责人: Grace Orstad
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159071
• 关键词: ATAC-seq; Adenocarcinoma Cell; Apoptosis; Binding; Binding Sites; CRISPR/Cas technology; Cancer Etiology; Cell Differentiation process; Cell Line; Cells; Cessation of life; ChIP-seq; Characteristics; Chromatin; Clinical; Complement; Country; DNA Binding Domain; DNA Sequence Alteration; Development; Diagnosis; Down-Regulation; Drug resistance; Exhibits; Foundations; Genes; Genetic Drift; Genetic Recombination; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomics; Grant; Growth; Heterogeneity; Human; Human Cell Line; In Vitro; KRAS2 gene; Lesion; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Morphology; Mus; Mutation; Neoplasm Metastasis; Organoids; Patients; Phenotype; Prognosis; Proliferation Marker; Regulator Genes; Regulatory Element; Resistance; Role; Testing; Tissues; Transcriptional Regulation; Tumor Burden; Tumor Escape; cancer type; clinical Diagnosis; cofactor; experimental study; genome editing; genome-wide; homeodomain; in vivo; insight; mouse model; mutant; neoplastic; neoplastic cell; novel; promoter; response; therapeutic development; transcription factor; transcriptome sequencing; transdifferentiation; tumor; tumor growth; tumor microenvironment; tumor progression

PROJECT ABSTRACT Lung cancer is the leading cause of cancer death worldwide. Although lung cancer rates have been steadily decreasing since the early 1990’s, it is still the deadliest cancer in the country, killing twice as many people in 2017 as the next four types of cancer combined. Lung adenocarcinoma is the most frequently diagnosed subtype of lung cancer, and approximately 25% of all LUAD cases are driven by Kras mutations. In patients, KRAS driven lung adenocarcinomas are significantly heterogeneous in cell identity and differentiation state; these characteristics correlate directly with patient prognosis and response to available therapies. Currently, the field lacks a comprehensive understanding of what governs LUAD cell identity and how these regulatory networks impact malignant potential. Identifying the master transcriptional regulators and the impact of their inactivation will provide novel insight into the mechanisms of cancer progression and lay the groundwork for the development of therapeutic strategies specific to tumor differentiation state. NKX2-1 is a master regulator of pulmonary identity in both healthy lung and neoplastic tissue. FOXA1 and FOXA2 (FOXA1/2) bind adjacent to NKX2-1 throughout the genome in both human and murine LUAD. NKX2-1 acts to retain a pulmonary differentiation state in LUAD in part by controlling FOXA1/2 binding at lineage-specific gene regulatory elements. FOXA1/2 directly interact with the DNA binding domain of NKX2-1; this interaction enhances NKX2-1 activity at promoters that also contain FOXA binding sites. It is also known that NKX2-1 coordinates with many other transcription factors and cofactors to facilitate the activation of lung- specific target genes. The objective of this grant is to identify cancer-relevant functions of FOXA1 and FOXA2 in lung adenocarcinomas that exhibit pulmonary differentiation by retaining NKX2-1 expression. We hypothesize that NKX2-1, FOXA1 and FOXA2 coordinately regulate growth, survival, and differentiation in LUAD. To test this hypothesis, we will examine how FOXA1 and FOXA2 govern LUAD cell identity and malignancy in established tumors, determine the impact of Foxa1/2 deletion on NKX2-1 transcriptional activity, and define the mechanisms by which tumors can escape the antiproliferative impact of Foxa1/2 deletion.

项目摘要 肺癌是全球癌症死亡的主要原因。虽然肺癌发病率 自20世纪90年代初以来一直在稳步下降，它仍然是该国最致命的癌症， 2017年患癌症的人数是接下来四种癌症人数总和的两倍。肺腺癌 是最常诊断的肺癌亚型，约25%的LUAD Kras基因突变导致的。在患者中，KRAS驱动的肺腺癌是 细胞特性和分化状态显著异质;这些特征与 与患者预后和对可用疗法的反应直接相关。目前，该领域缺乏 全面了解是什么支配LUAD细胞的身份，以及如何这些 监管网络影响恶性潜力。识别主转录本 调节因子及其失活的影响将提供新的洞察机制， 癌症进展，并为制定治疗策略奠定基础， 到肿瘤分化状态。NKX 2 -1是两种健康人中肺特性的主要调节剂。 肺和肿瘤组织。FOXA 1和FOXA 2（FOXA 1/2）在整个过程中与NKX 2 -1相邻结合 人和鼠LUAD的基因组。NKX 2 -1起保持肺分化的作用 在LUAD中的状态部分通过控制FOXA 1/2在谱系特异性基因调控元件的结合。 FOXA 1/2直接与NKX 2 -1的DNA结合结构域相互作用;这种相互作用增强了 NKX 2 -1在也含有FOXA结合位点的启动子处的活性。据了解，NKX 2 -1 与许多其他转录因子和辅因子协调，以促进肺的激活， 特定的靶基因。该基金的目的是确定FOXA 1的癌症相关功能。 在肺腺癌中通过保留NKX 2 -1而表现出肺分化 表情我们假设NKX 2 -1、FOXA 1和FOXA 2协同调节生长， 生存和分化。为了验证这一假设，我们将研究FOXA 1和 FOXA 2在已建立的肿瘤中控制LUAD细胞的身份和恶性程度，确定FOXA 2的影响。 Foxa 1/2缺失对NKX 2 -1转录活性的影响，并确定肿瘤发生的机制。 可以逃避Foxa 1/2缺失的抗增殖作用。