The Role of Secondary Bile Acids in Gastro-Esophageal Neoplasia

次级胆汁酸在胃食管肿瘤中的作用

• 批准号: 10693227
• 负责人: Julian Abrams
• 金额: $ 81.24万
• 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/10693227
• 关键词: Acceleration; Acids; Address; Adenocarcinoma; Affect; Agonist; Area; Barrett Esophagus; Bile Acids; Cell Count; Cells; Cessation of life; Collaborations; Data; Deoxycholic Acid; Development; Distal; Dysplasia; Epithelial Attachment; Esophageal Adenocarcinoma; Esophagogastric Junction; Esophagus; Future; High Fat Diet; Human; Immune; Inflammasome; Inflammation; Inflammatory; Knock-out; Knowledge; LGR5 gene; Malignant Neoplasms; Modeling; Modification; Molecular; Mus; Myeloid Cells; Natural Killer Cells; Neoplasms; Nuclear; Organoids; Patients; Population; Precancerous Conditions; Production; Proliferating; Prospective Studies; Public Health; Regional Cancer; Risk Factors; Role; Sampling; Series; Stomach; Stromal Cells; Techniques; Translating; Validation; Work; antagonist; carcinogenesis; chemokine; clinically significant; cohort; epithelial stem cell; experimental study; gastroesophageal cancer; gut bacteria; gut microbiome; microbiome; microbiome composition; mortality; mouse model; multidisciplinary; neutrophil; new therapeutic target; novel; novel strategies; prevent; probiotic therapy; prototype; rational design; receptor; single-cell RNA sequencing; spatiotemporal; stem; stem cell fate; stem cells; stomach cardia

PROJECT SUMMARY Stem and progenitor cells at the gastroesophageal junction (GEJ) have been identified as crucial to the development of adenocarcinoma of the distal esophagus, gastroesophageal junction, and proximal stomach. Combined, these cancers have over 20,000 new cases per year in the U.S., are associated high mortality, and represent a major public health burden. Our group has identified both gastric cardia as well as GEJ transitional basal stem cells as likely cells of origin for precancerous states in this region. However, defining the mechanisms and effectors that drive GE junction stem cell fate and promote cancer development remains a critical gap in knowledge. Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) represent the prototype for neoplasia arising from GE junction stem cells. We have extensive preliminary data demonstrating that circulating secondary bile acids derived from gut bacteria directly promote the development of BE and EAC, treating our L2-IL1B mouse model of BE/EAC with deoxycholic acid (DCA) accelerates neoplasia, and treatment with obeticholic acid, an agonist of nuclear bile acid receptor FXR (farnesoid X receptor), decreases proliferation, GEJ stem cell numbers, and dysplasia. However, the exact mechanisms by which secondary bile acids impact GEJ stem cells and the associated microenvironment have not been elucidated. We hypothesize that circulating secondary bile acids produced by gut bacteria promote early cancer development via direct effects on GE junction stem cells through FXR antagonism and by inducing pro-inflammatory microenvironment alterations. Using highly novel techniques and approaches (including scRNA-Seq and CyTOF), we will perform a series of experiments using mouse models, mouse and human organoids, and with validation of findings in a prospective study of patients, to address the following specific aims: Aim 1. To determine the role of circulating secondary bile acids in GEJ epithelial stem cell fate and early cancer promotion; Aim 2. To assess the effects of circulating secondary bile acids on the GEJ epithelial stem cell microenvironment; Aim 3. To determine whether targeted microbiome modification that regulates the circulating bile acid pool modifies GEJ cancer development. To achieve these aims we will use our unique L2-IL1B mouse model with FXR knockout in stem cells (L2- IL1B/Fxrfl/fl), allowing us to assess the effects of secondary bile acids on GEJ stem cells as well the L2-IL1B/Nlrpfl/fl model to explore inflammasome activation in stem cells and assess for cross-talk with the microenvironment. Ultimately, we will perform experiments treating with distinct consortia of highly characterized bacterial strains to modulate the secondary bile acid producing capacity of the gut microbiome and determine the effects on cancers arising from GE junction stem cells. Elucidation of the specific mechanisms by which secondary bile acids interact with GEJ stem cells and modify the microenvironment to promote cancer development may lead to the identification of novel therapeutic targets, including the potential for rationally designed probiotic therapy, which would have a major public health impact.

项目摘要 胃食管治疗（GEJ）处的茎和祖细胞已被确定为对 食管远端，胃食管结和胃近端的腺癌的发展。 这些癌症在美国每年有超过20,000例新病例，与高死亡率相关，并且 代表一个主要的公共卫生伯恩。我们的小组已经确定了胃Cardia和GEJ过渡 基本干细胞作为该区域癌前状态的原始细胞。但是，定义机制 以及驱动GE连接干细胞命运和促进癌症发展的影响仍然是一个关键的差距 知识。巴雷特的食道（BE）和食道腺癌（EAC）代表原型 GE连接干细胞引起的肿瘤。我们有广泛的初步数据，表明循环 源自肠道细菌的次生胆汁酸直接促进BE和EAC的发展，以治疗我们 用脱氧胆酸（DCA）的BE/EAC的L2-IL1B小鼠模型加速了肿瘤，并与 核酸受体FXR（Farnesoid X受体）的激动剂Obeticholic Acid下降了增殖， GEJ干细胞数和发育不良。但是，次级胆汁酸会影响的确切机制 GEJ干细胞和相关的微环境尚未阐明。我们假设这是循环的 肠道细菌产生的继发性胆汁酸会通过直接影响GE促进早期癌症发展 连接干细胞通过FXR拮抗作用和诱导的促炎性微环境改变。 使用高度新颖的技术和方法（包括SCRNA-SEQ和CYTOF），我们将执行一系列 使用鼠标模型，小鼠和人类器官进行实验，并在前瞻性中验证发现 研究患者，以解决以下特定目的：目标1。确定循环次级的作用 GEJ上皮干细胞命运和早期癌症促进中的胆汁酸；目标2。评估循环的影响 GEJ上皮干细胞微环境上的次生胆汁酸；目标3。确定是否针对 调节循环胆酸池的微生物组修饰可修饰GEJ癌症的发展。到 达到这些目标，我们将使用我们独特的L2-IL1B小鼠模型与干细胞中的FXR敲除（L2-- IL1b/fxrfl/fl），使我们能够评估二级胆汁酸对GEJ干细胞的影响以及L2-IL1B/NLRPFL/FL 探索干细胞中炎症体激活并评估与微环境的互相对话的模型。 最终，我们将用高度特征的细菌菌株进行实验治疗 调节肠道微生物组的次级胆汁酸产能，并确定对 由GE连接干细胞引起的癌症。阐明次级胆汁的特定机制 酸与GEJ干细胞相互作用并修改微环境以促进癌症发展 确定新型治疗靶标，包括进行合理设计的益生菌治疗的潜力 这将产生重大的公共卫生影响。