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

项目摘要 肺癌是全球癌症死亡的主要原因。尽管肺癌的发病率 自20世纪90年代初以来一直在稳步下降，S，它仍然是中国最致命的癌症，导致 2017年的人数是紧随其后的四种癌症总和的两倍。肺腺癌 是最常见的肺癌亚型，约占所有LUAD的25% 病例是由Kras突变引起的。在患者中，KRAS驱动的肺腺癌是 细胞身份和分化状态明显不同；这些特征相互关联 直接与患者的预后和对现有治疗的反应有关。目前，该领域缺乏一个 全面了解管理LUAD小区身份的是什么以及如何 监管网络影响恶性潜在性。鉴定主要转录产物 调节器及其失活的影响将提供对 并为制定特定的治疗策略奠定了基础 至肿瘤分化状态。Nkx2-1是两种健康人肺特性的主要调节因子 肺和肿瘤组织。FOXA1和FOXA2(FOXA1/2)始终与NKX2-1相邻结合 人类和小鼠LUAD的基因组。Nkx2-1在肺分化中的作用 LUAD的状态部分是通过控制FOXA1/2与谱系特异的基因调控元件的结合来实现的。 FOXA1/2直接与NKX2-1的DNA结合域相互作用；这种相互作用增强 也包含FOXA结合位点的启动子上的Nkx2-1活性。另据了解，NKX2-1 与许多其他转录因子和辅因子协调，促进肺- 特定的靶基因。这项资助的目的是确定FOXA1与癌症相关的功能 和FOXA2在保留NKX2-1表现为肺分化的肺腺癌中的表达 表情。我们假设NKX2-1、FOXA1和FOXA2协调调节生长， 在LUAD中的存活和分化。为了验证这一假设，我们将检查FOXA1和 FOXA2控制LUAD细胞特性和已建立的肿瘤的恶性度，确定 FOXA1/2缺失对NKX2-1转录活性的影响，并确定肿瘤 可以逃脱FOXA1/2缺失的抗增殖影响。

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.