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.

项目概要 巴雷特食管（BE）及其恶性食管腺癌的发病率迅速增加 (EAC)，交界性胃癌已在美国造成严重的健康和经济负担。迄今为止， 这些疾病的有效治疗方案受到限制，部分原因是对这些疾病的了解不完全。 驱动初始化生和随后的肿瘤进展的分子机制。 两位具有互补专业知识的 PI 寻求通过结合 scRNA 测序分析来解决该问题， 创新的BE小鼠模型和类器官建模我们之前证明了胃贲门祖细胞。 细胞和移行基底细胞 (TBC) 导致胃食管交界处移行区的 BE (GEJ).然而，这些祖细胞在BE-发育不良-EAC进展中的表现仍不清楚。 此外，我们的初步数据也不清楚驱动疾病进展的分子机制。 表明 GEJ 化生及其向 EAC 的进展涉及 p53 丢失促进的祖细胞可塑性， 此外，我们发现 Barrett 化生和 EAC 与 BE 的早期遗传病变有关。 因此，我们敢于认为 Barrett 化生和发育不良源自 GEJ。 祖细胞，受 p53 突变和簇细胞扩张调节的三个具体目标是。 制定测试假设：目标 1 是确定 BE 化生的起源和进化 目标 2 是阐明 p53 突变促进 BE 的机制。 目的3是结合我们的关节阐明簇细胞在BE发病机制和进展中的作用。 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，这项工作将提供新颖的 对巴雷特化生及其恶性进展机制的深入见解，提供 治疗这些疾病的新方法。