Cell-of-Origin Footprints of Passenger Mutations in Human Lung Cancer

人类肺癌中乘客突变的细胞起源足迹

• 批准号: 10871512
• 负责人: Marcin Imielinski
• 金额: $ 52.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10871512
• 关键词: ATAC-seq; Address; Affect; Alleles; Alveolar; Atlases; Basal Cell; Benign; Cancer Biology; Cancer Etiology; Carcinoma; Cells; Cessation of life; Chromatin; Classification; Clinical; DNA sequencing; Data; Development; Disease model; Disseminated Malignant Neoplasm; Distal; Epigenetic Process; Epithelium; Event; Gene Expression; Gene Proteins; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomics; Genotype; Goblet Cells; Hematologic Neoplasms; Hematopoietic Neoplasms; Histologic; Histology; Human; Individual; Knowledge; Link; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Modeling; Morphology; Mutation; Neuroendocrine Cell; Normal Cell; Outcome; Patients; Pattern; Pharmaceutical Preparations; Prognosis; Research; STK11 gene; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Somatic Mutation; Sorting; Stress; Study models; Tattooing; Testing; Therapeutic; Tissues; Tumor Biology; Untranslated RNA; Woman; Work; alveolar type II cell; benign state; blood treatment; cancer cell; cancer subtypes; cancer type; cell type; clinically significant; cohort; driver mutation; genome sequencing; genome-wide; insertion/deletion mutation; insight; mouse model; mutant; mutational status; never smoker; novel; novel strategies; response; single cell sequencing; single-cell RNA sequencing; standard of care; surfactant; targeted sequencing; tumor; tumor progression; whole genome

Project summary / abstract The normal cell of origin (COO) from which a cancer arises is fundamental to our basic notions of cancer development. COOs are central to the standard of care for hematopoietic cancers, where they inform prognosis and guide therapy. However, COOs are not incorporated into the clinical paradigms for treating lung adenocarcinomas, an epithelial cancer that is among the leading causes of cancer death worldwide. The major reason for this is that we still don’t know the COO for most lung adenocarcinomas or whether the COO varies from patient to patient. One major scientific obstacle to addressing this question is the limited understanding of lung cell types, and epithelial types in general. A second obstacle is lineage infidelity that occurs during lung cancer progression, which can obscure the COO when one analyzes tumors morphologically or transcriptionally. As a result, the field has been required to rely on genetically engineered mouse models, which are still limited in their ability to fully recapitulate genotypes and clinical features of human lung adenocarcinomas. Recent work by us and others in the field has shown that genome-wide patterns of passenger mutations can provide a patient-specific COO signal. However, this hypothesis has not been tested rigorously for lung cancer or for other malignancies. In this study, we investigate how passenger mutation patterns inform COOs in lung cancer. In particular, we focus on noncoding surfactant protein gene (SPG) insertions and deletions, which our recent study (Cell 2017) and preliminary data establishes as one of the most common mutational events in lung adenocarcinoma (30-40% of patients). In this study, we hypothesize that this mysterious but highly prevalent mutational pattern is a somatic genetic “tattoo” of alveolar type II (AT2) cell origin in SPG mutant lung adenocarcinomas. We will investigate this through deep profiling of tumor adjacent tissue using targeted and single cell sequencing. In addition, we will investigate whether SPG mutant lung adenocarcinomas are associated with distinct evolutionary trajectories, with respect to their mutational, transcriptional, and histological state. Finally, we will build on our preliminary studies that establish compelling links between genome distributions of somatic single nucleotide variants (SNVs) in lung cancer and cell-type specific gene expression profiles obtained from single-cell RNA sequencing of benign lung. These preliminary data indicate that some lung adenocarcinomas may have proximal (club or basal cell) rather than distal (AT2 cell) origins. We will build on our initial findings, to generate and analyze higher depth atlases of healthy lung and correlate the patterns of cell type specific transcriptional and open chromatin profiles with genomic distributions of somatic SNVs. This work will provide some of the first direct evidence to map human lung adenocarcinoma to specific COOs. Furthermore, our establishment of rigorous links between passenger mutational patterns and COO in lung cancer may have broader applicability to the study of COOs in other prevalent and deadly human epithelial cancers.

项目概要/摘要 癌症产生的正常起源细胞 (COO) 是我们癌症基本概念的基础 发展。 COO 是造血系统癌症护理标准的核心，他们告知 预后并指导治疗。然而，COO 并未纳入治疗肺病的临床范例中。 腺癌是一种上皮癌，是全世界癌症死亡的主要原因之一。主要 原因是我们仍然不知道大多数肺腺癌的 COO 或 COO 是否有所不同 从一个病人到另一个病人。解决这个问题的一个主要科学障碍是对 肺细胞类型和一般上皮类型。第二个障碍是在肺病期间发生的血统不忠。 癌症进展，当人们对肿瘤进行形态学或分析时，这可能会掩盖 COO 转录地。因此，该领域需要依赖基因工程小鼠模型， 其完全重现人肺基因型和临床特征的能力仍然有限 腺癌。我们和该领域其他人最近的工作表明，全基因组模式 乘客突变可以提供患者特异性的 COO 信号。然而，这一假设尚未得到检验 严格针对肺癌或其他恶性肿瘤。在这项研究中，我们研究了乘客突变如何 模式为肺癌首席运营官提供信息。我们特别关注非编码表面活性蛋白基因（SPG） 插入和删除，我们最近的研究（Cell 2017）和初步数据将其确定为插入和删除之一 肺腺癌（30-40% 的患者）中最常见的突变事件。在这项研究中，我们假设 这种神秘但高度普遍的突变模式是 II 型肺泡 (AT2) 的体细胞遗传“纹身” SPG突变肺腺癌的细胞起源。我们将通过对肿瘤的深入分析来研究这一点 使用靶向和单细胞测序来检测邻近组织。此外，我们将调查SPG是否突变 肺腺癌与不同的进化轨迹相关，就其突变而言， 转录和组织学状态。最后，我们将在初步研究的基础上建立令人信服的 肺癌体细胞单核苷酸变异（SNV）的基因组分布与细胞类型之间的联系 从良性肺的单细胞 RNA 测序中获得的特定基因表达谱。这些初步的 数据表明，一些肺腺癌可能具有近端（俱乐部或基底细胞）而不是远端（AT2 细胞）起源。我们将在初步发现的基础上，生成和分析更高深度的健康肺部图谱 并将细胞类型特异性转录模式和开放染色质谱与基因组相关联 体细胞 SNV 的分布。这项工作将为绘制人类肺部地图提供一些第一个直接证据 腺癌特定 COO。此外，我们在乘客之间建立了严格的联系 肺癌中的突变模式和 COO 可能对其他癌症的 COO 研究具有更广泛的适用性 普遍且致命的人类上皮癌。