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

基本信息

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
项目类别：
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

项目摘要

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 COO 是造血系统癌症护理标准的核心，他们提供信息。然而，COO 并未纳入肺部治疗的临床范例中。腺癌是一种上皮癌，是全世界癌症死亡的主要原因之一。原因是我们仍然不知道大多数肺腺癌的 COO 或 COO 是否有所不同解决这个问题的一个主要科学障碍是对患者的理解有限。肺细胞类型和一般上皮类型的第二个障碍是肺细胞中发生的谱系不忠。癌症进展，当一个双胞胎肿瘤在形态或形态上时，这可能会掩盖 COO 因此，该领域需要依赖基因工程小鼠模型，完全重现人肺基因型和临床特征的能力仍然有限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。在这项研究中，我们研究了乘客突变是如何发生的。模式为肺癌 COO 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。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” 我们将通过对肿瘤的深入分析来研究 SPG 突变肺腺癌的细胞起源。使用靶向和单细胞测序的邻近组织此外，我们将研究SPG是否突变。肺腺癌与不同的进化轨迹相关，就其突变而言，最后，我们将建立令人信服的初步研究。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这些初步的基因表达谱是从良性肺部的单细胞RNA测序中获得的。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 我们将在初步发现的基础上，生成并分析健康肺部的更高深度图谱。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这项工作将为绘制人类肺部图谱提供一些第一个直接证据。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 可能对其他疾病的 COO 研究具有更广泛的适用性普遍且致命的人类上皮癌。