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: 10537529
• 负责人: Katherine L Gillis
• 金额: $ 4.68万
• 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/10537529
• 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; Mitogen-Activated Protein Kinases; Molecular; Morphology; Mucous Membrane; Mus; Organoids; Pathogenesis; Pathway interactions; Pharmacology; Post-Translational Protein Processing; Publishing; Regulatory Element; Role; Signal Transduction; Small Cell Carcinoma; Stomach; Structure; Surface; Survival Rate; Testing; Therapeutic; Therapeutic Intervention; Tissue Differentiation; Tissue-Specific Gene Expression; Transcript; Tumor-Derived; Woman; Work; cancer cell; chemotherapy; chromatin modification; cofactor; demethylation; disorder subtype; drug development; epigenetic regulation; experimental study; insight; loss of function; men; mortality; mutant; novel; patient prognosis; personalized medicine; 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的主要原因。尽管筛选方面取得了进步 方法和个性化治疗，患者预后仍然很差，5 年生存率从 4- 17%。肺腺癌 (LUAD) 是这种疾病最常诊断的亚型，具有显着的 其细胞身份或组织分化状态的异质性。细胞身份的变化已被证明 与临床参数密切相关，包括患者预后、对化疗的敏感性以及 耐药性的发展。目前，该领域缺乏对分子的全面了解。 调节肺腺癌细胞身份和控制肿瘤进展的网络。识别 主转录调节因子将为癌症进展机制提供新的见解并奠定基础 开发针对肿瘤分化状态的治疗策略的基础。 侵袭性粘液腺癌 (IMA) 是 LUAD 的一种亚型，具有肺至胃谱系 在其自然进展过程中进行切换。使用基因工程小鼠模型，我们发现损失 肺谱系特异因子 NKX2-1/TTF1 导致 LUAD 胃转分化，产生小鼠 概括了人类 IMA 的形态和基因表达谱的肿瘤。这种胃谱系转换 部分由先驱因子 FoxA1 和 FoxA2 (FoxA1/2) 的差异染色质结合介导， 在整个基因组中从肺部基因座重新定位到胃基因的调节元件。 NKX2-1 丢失后， 这些胃基因还经历与基因激活相关的染色质修饰，包括增加 组蛋白 3 赖氨酸 27 乙酰化 (H3K27ac)。然而，尚不清楚 FoxA1/2 是否需要 在其从头结合位点介导这些染色质改变，从而促进肿瘤谱系 交换。除了调节肺胃转分化外，FoxA1/2 还调节 LUAD 对靶向治疗的反应的身份。丝裂原激活蛋白激酶的药理学抑制 信号级联不仅导致 NKX2-1 阴性 LUAD 中的肿瘤消退，而且还导致胃 依赖于 FoxA1/2 活性的谱系转换。因此，本提案的目标是确定 FoxA1/2 调节 NKX2-1 阴性 LUAD 染色质景观的机制 癌症身份。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。为了检验这个假设，我们将确定是否 在已建立的肿瘤中 Nkx2-1 缺失后，FoxA1/2 是染色质调节所必需的，并定义了 FoxA1/2 介导这些变化的精确机制。该提案意义重大，因为它将提供 更深入地了解调节 LUAD 细胞身份和肿瘤进展的分子网络， 对于制定亚型特异性干预措施至关重要的发现。