Gastroesophageal junction stem cells as the origin of Barretts esophagus and cancer

胃食管连接处干细胞是巴雷特食管和癌症的起源

• 批准号: 10506097
• 负责人: Jianwen Que
• 金额: $ 97.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506097
• 关键词: 3-Dimensional; ATAC-seq; Acceleration; Address; Adenocarcinoma; Affect; Automobile Driving; Barrett Esophagus; Basal Cell; Bile Acids; Biology; Cell physiology; Cells; Cellular biology; Cessation of life; Characteristics; Chromatin; Chronic; Clonal Evolution; Country; DNA Damage; Data; Development; Disease; Disease Progression; Distal; Dysplasia; Dysplasia in Barrett' s Esophagus; Epithelial Attachment; Esophageal Adenocarcinoma; Esophagitis; Esophagogastric Junction; Esophagus; Evolution; Financial Hardship; Gastric Adenocarcinoma; Gastroesophageal reflux disease; Gene Expression Profile; Genetic; Genetic Determinism; Genomics; Health; Human; In Vitro; Incidence; Inflammation; Inflammatory Response; Injury; Intestines; Joints; Knowledge; Lesion; Lymphoid Cell; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Metaplasia; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Obesity; Organoids; Pathogenesis; Pathway interactions; Patients; Population; Pre-Clinical Model; Resistance; Risk; Risk Factors; Role; Side; Simple Columnar Epithelium; Specific qualifier value; Stomach; TP53 gene; Testing; Tissues; Transitional Epithelium; Work; cancer type; carcinogenesis; carcinogenicity; cytokine; effective therapy; epigenomics; feeding; in vivo; innovation; insight; malignant stomach neoplasm; molecular phenotype; mouse genetics; mouse model; mutant; novel; novel strategies; novel therapeutics; progenitor; response; single-cell RNA sequencing; stem; stem cell differentiation; stem cells; stem-like cell; stomach cardia; transcriptome sequencing; tumor; tumor progression

Project Summary The rapid increase in the incidence of Barrett’s esophagus (BE), its malignant form esophageal adenocarcinoma (EAC), and junctional gastric cancer has produced serious health and financial burdens in the U.S. Thus far, effective treatment options for these diseases are limited in part due to an incomplete understanding of the molecular mechanisms driving the initial metaplasia and subsequent neoplastic progression. This application, by two PIs with complementary expertise, seeks to address the issue through combining scRNA-sequencing analysis, innovative BE mouse models and organoid modeling. We previously demonstrated that gastric cardia progenitor cells and transitional basal cell (TBCs) contribute to BE in the transitional zone of the gastro-esophageal junction (GEJ). However, how these progenitor cells behave in BE-dysplasia-EAC progression remains unclear. Additionally, the molecular mechanism driving the disease progression is also unknown. Our preliminary data suggest GEJ metaplasia and its progression towards EAC involves progenitor plasticity facilitated by p53 loss, an early genetic lesion in BE. Furthermore, we found that Barrett’s metaplasia and EAC is associated with the enrichment of tuft cells. Therefore we hypothesize that Barrett’s metaplasia and dysplasia originate from GEJ progenitor cells, modulated by the presence of p53 mutation and tuft cell expansion. Three specific aims are formulated to test the hypothesis: Aim 1 is to determine the origins and evolution of BE metaplasia from progenitor cells at the EGJ. Aim 2 is to elucidate the mechanisms by which p53 mutation promotes BE progression, and Aim 3 is to clarify the role of tuft cells in BE pathogenesis and progression. Combining our joint expertise on mouse genetics, cell biology, chromatin biology and epigenomics, this work will provide novel mechanistic insights into the mechanisms underlying Barrett’s metaplasia and its malignant progression, offering new approaches to treat these diseases.

项目摘要 Barrett食管（BE）的发病率迅速增加，其恶性形式为食管腺癌， (EAC)和交界性胃癌已经在美国产生了严重的健康和经济负担。到目前为止， 对这些疾病的有效治疗选择是有限的，部分原因是对这些疾病的不完全理解。 驱动初始化生和随后的肿瘤进展的分子机制。本申请书，由 两个专业知识互补的PI，试图通过结合scRNA测序分析来解决这个问题， 创新的BE小鼠模型和类器官建模。我们以前证明贲门祖细胞 在胃食管交界处的移行带中，基底细胞和移行基底细胞（TBCs）参与BE （GEJ）。然而，这些祖细胞如何在BE-发育不良-EAC进展中表现仍不清楚。 此外，驱动疾病进展的分子机制也是未知的。我们的初步数据 提示GEJ化生及其向EAC的进展涉及p53缺失促进的祖细胞可塑性， BE的早期遗传损伤。此外，我们发现Barrett化生和EAC与肿瘤的发生有关。 富集簇状细胞。因此我们推测Barrett化生和发育不良起源于GEJ 祖细胞，由p53突变和簇细胞扩增的存在调节。三个具体目标是 制定来检验假设：目的1是确定BE化生的起源和演变， 在EGJ的祖细胞。目的二是阐明p53突变促进BE的机制 目的3是阐明丛状细胞在BE发病机制和进展中的作用。结合我们的联合 在小鼠遗传学，细胞生物学，染色质生物学和表观基因组学方面的专业知识，这项工作将提供新的 对Barrett化生及其恶性进展的机制的机械见解， 治疗这些疾病的新方法。