Epigenetic regulation of NKX2-1-negative lung adenocarcinoma cellular identity by FoxA1 and FoxA2

FoxA1 和 FoxA2 对 NKX2-1 阴性肺腺癌细胞身份的表观遗传调控

• 批准号: 10666426
• 负责人: Katherine L Gillis
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10666426
• 关键词: ATAC-seq; Acetylation; Adenocarcinoma; Adenocarcinoma Cell; Alleles; Appendix Adenocarcinoma; Binding; Binding Sites; Biological Assay; Cancer Control; Cancer Etiology; Cells; ChIP-seq; Characteristics; Chief Cell; Chromatin; Clinical; DNA; DNA Methylation; Deposition; Development; Diagnosis; Drug resistance; EP300 gene; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Exhibits; Gastric Chief Cells; Gene Activation; Gene Expression Profile; Genes; Genetic Transcription; Genetically Engineered Mouse; Genome; Heterogeneity; Histones; Human; In Vitro; Intervention; KRAS2 gene; Knowledge; LGR5 gene; Link; Lung; Lung Adenocarcinoma; Lysine; Malignant - descriptor; Malignant neoplasm of lung; Mediating; Methods; Methylation; Mitogen-Activated Protein Kinases; Molecular; Morphology; Mucous Membrane; Mus; Organoids; Pathogenesis; Pathway interactions; Post-Translational Protein Processing; Publishing; Regulatory Element; Role; Signal Transduction; Small Cell Carcinoma; Specific qualifier value; Stomach; Structure; Surface; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Tissue Differentiation; Tissue-Specific Gene Expression; Transcript; Tumor Escape; Tumor-Derived; Woman; Work; acquired drug resistance; cancer cell; chemotherapy; chromatin modification; cofactor; demethylation; disorder subtype; drug resistance development; epigenetic regulation; experimental study; insight; loss of function; men; mortality; mutant; novel; patient prognosis; personalized medicine; pharmacologic; programs; recruit; response; screening; targeted treatment; therapeutic development; transcription factor; transdifferentiation; treatment response; tumor; tumor progression

PROJECT ABSTRACT Lung cancer is the leading cause of cancer mortality in both men and women. Despite advances in screening methods and personalized therapy, patient prognosis remains dismal with 5-year survival rates varying from 4- 17%. Lung adenocarcinoma (LUAD), the most frequently diagnosed subtype of this disease, exhibits substantial heterogeneity in its cellular identity or tissue differentiation state. Changes in cellular identity have been shown to strongly correlate with clinical parameters including patient prognosis, sensitivity to chemotherapy, and development of drug resistance. Currently, the field lacks a comprehensive understanding of the molecular networks that regulate lung adenocarcinoma cell identity and govern tumor progression. Identifying master transcriptional regulators 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. Invasive mucinous adenocarcinoma (IMA) is a subtype of LUAD that undergoes pulmonary to gastric lineage switching during its natural progression. Using genetically engineered mouse models, we have found that loss of the pulmonary lineage specifier NKX2-1/TTF1 causes gastric transdifferentiation in LUAD, generating murine tumors that recapitulate the morphology and gene expression profile of human IMA. This gastric lineage switch is mediated in part by differential chromatin binding of pioneer factors, FoxA1 and FoxA2 (FoxA1/2), which relocate throughout the genome from pulmonary loci to regulatory elements of gastric genes. Upon NKX2-1 loss, these gastric genes also undergo chromatin modifications associated with gene activation including increases in histone 3 lysine 27 acetylation (H3K27ac). However, it is unknown whether FoxA1/2 are required to mediate these chromatin alterations at their de novo binding sites and thereby, facilitate tumor lineage switching. In addition to regulating the pulmonary-to-gastric transdifferentiation, FoxA1/2 also modulate LUAD identity in response to targeted therapy. Pharmacologic inhibition of the mitogen-activated protein kinase signaling cascade not only causes tumor regression in NKX2-1-negative LUAD, but also results in a gastric lineage switch that is dependent upon FoxA1/2 activity. Thus, the objective of this proposal is to determine the mechanism by which FoxA1/2 modulate the chromatin landscape of NKX2-1-negative LUAD in order to control cancer identity. The central hypothesis is that FoxA1/2 restructure chromatin accessibility and modify the histone/ DNA methylation landscape in order to control LUAD identity. To test this hypothesis, we will determine whether FoxA1/2 are required for chromatin modulation following Nkx2-1 deletion in established tumors and define the precise mechanism by which FoxA1/2 mediate these changes. This proposal is significant because it will provide a deeper understanding of the molecular networks that regulate LUAD cellular identity and tumor progression, findings which are essential for the development of subtype-specific interventions.

项目摘要 肺癌是男性和女性癌症死亡率的主要原因。尽管筛选进展 方法和个性化疗法，患者预后仍然令人沮丧，5年生存率从4-- 17％。肺腺癌（LUAD）是该疾病最常诊断的亚型，表现出大量 其细胞身份或组织分化状态的异质性。已经显示了细胞身份的变化 与临床参数密切相关，包括患者预后，对化疗的敏感性和 耐药性的发展。目前，该领域对分子缺乏全面的理解 调节肺腺癌细胞身份并控制肿瘤进展的网络。识别 主要的转录调节器将提供有关癌症进展机制的新洞察力 开发针对肿瘤分化状态的治疗策略的基础。 浸润性粘液腺癌（IMA）是LUAD的亚型 在自然进展过程中切换。使用基因工程的鼠标模型，我们发现了损失 肺谱系指定剂NKX2-1/TTF1引起luad的胃转变，产生鼠 概括了人IMA的形态和基因表达谱的肿瘤。这个胃谱系开关 一部分是由先锋因素的差异染色质结合，FOXA1和FOXA2（FOXA1/2）介导的， 整个基因组从肺地基因座转移到胃基因的调节元件。在NKX2-1损失后， 这些胃基因还经历了与基因激活相关的染色质修饰，包括增加 在组蛋白3赖氨酸27乙酰化（H3K27AC）中。但是，尚不清楚是否需要FOXA1/2 调解这些从头结合位点的这些染色质改变，从而促进肿瘤谱系 交换。除了调节肺到冬季跨分化外，FOXA1/2还调节LUAD 响应靶向治疗的身份。有丝分裂原激活蛋白激酶的药理抑制 信号级联不仅会导致NKX2-1阴性LUAD的肿瘤回归，而且还会导致胃 谱系开关取决于FOXA1/2活动。因此，该提议的目的是确定 FOXA1/2调节NKX2-1阴性LUAD的染色质景观以控制的机制 癌症认同。中心假设是FOXA1/2重组染色质可及性并修改组蛋白/ DNA甲基化景观以控制LUAD身份。为了检验这一假设，我们将确定是否 在既定肿瘤中NKX2-1删除后，染色质调制需要FOXA1/2，并定义 FOXA1/2介导这些变化的精确机制。该提议很重要，因为它将提供 对调节LUAD细胞身份和肿瘤进展的分子网络的更深入了解， 对于开发亚型特异性干预措施至关重要的发现。