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.

项目摘要 /摘要 产生癌症的正常原始细胞（COO）对于我们的癌症基本注释至关重要 发展。 COO是造血癌的护理标准的核心，他们在那里告知 预后和指导疗法。但是，COO未纳入治疗肺的临床范例 腺癌是一种上皮癌，是全球癌症死亡的主要原因之一。专业 原因是我们仍然不知道大多数肺腺癌的首席运营官，还是COO品种 从病人到病人。解决这个问题的一个主要科学障碍是对 肺部细胞类型和上皮类型通常。第二个障碍是肺部发生的谱系不忠 癌症的进展，当一个人通过形态学分析肿瘤或 转录。结果，该领域被要求依靠一般工程的鼠标模型， 它们完全概括了人类肺的基因型和临床特征的能力仍然有限 腺癌。我们和该领域的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。但是，该假设尚未进行检验 严格用于肺癌或其他恶性肿瘤。在这项研究中，我们研究了乘客突变 模式为肺癌中的COO提供了信息。特别是，我们专注于非编码表面活性剂蛋白基因（SPG） 插入和缺失，我们最近的研究（Cell 2017）和初步数据确定为 肺腺癌中最常见的突变事件（30-40％的患者）。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肺泡II型的躯体遗传“纹身”（AT2） SPG突变肺腺癌中的细胞来源。我们将通过对肿瘤的深度分析进行调查 使用靶向和单细胞测序的邻近组织。此外，我们将研究SPG突变体是否 肺腺癌与它们的突变有关，与不同的进化轨迹有关 转录和组织学状态。最后，我们将基于我们的初步研究来建立引人注目的 肺癌和细胞类型中体细胞核苷酸变体（SNV）的基因组分布之间的联系 从良性肺的单细胞RNA测序获得的特定基因表达谱。这些初步 数据表明某些肺腺癌可能具有近端（俱乐部或基本细胞）而不是远端（AT2） 细胞）起源。我们将基于我们的初步发现，以产生和分析健康肺的更高深度地图 并将细胞类型特异性转录和开放染色质曲线的模式与基因组相关联 躯体SNV的分布。这项工作将为绘制人肺的第一个直接证据提供 腺癌到特定的coos。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可能对其他在其他的COO研究更广泛地适用于其他 流行而致命的人类上皮癌。