Mechanisms underlying gastric intestinal metaplasia and carcinogenesis

节目概要 胃癌或GC（包括胃食管连接部癌）是第五大最常见的诊断 全球癌症据报道，胃癌的发病率和死亡率在不同年龄段之间存在显著差异。 种族/民族团体。在美国，非西班牙裔黑人（NHB），西班牙裔（USH）和非西班牙裔亚洲人或 太平洋岛民（NHAPI）更常被诊断为胃癌， 非西班牙裔白人（NHW）肠上皮化生（IM）是一个关键的前体胃癌的中间阶段 发育不良胃IM多出现在胃窦-胃体交界处，特别是在切迹处; 胃IM也可发生在贲门。导致胃IM发展的因素包括胆汁反流 吸烟、饮酒、高盐摄入与H。幽门感染IM在胃和胃中的标志 食管（=Barrett食管）是细胞特性改变为柱状肠型上皮， 这表明IM在这两个器官中具有共同的机制。CDX 2等几个关键转录因子 在功能上需要启动IM，可能与其他因素和涉及表观遗传 重新编程我们提出的研究的主要目标是解决该领域的根本差距（1）如何 胃IM出现？(2)在贲门和胃窦是否有共同的分子途径引发IM？（三） TP 53肿瘤抑制基因突变和炎症因子是如何导致IM的发生的？ 我们将采用互补的创新平台诱导多能干细胞（iPSC）模型，3D 来自胃IM患者的类器官，并将这些类器官与成纤维细胞和免疫细胞共培养， 破译微环境线索如何催化从化生到异型增生和GEJ/胃 腺癌我们试图了解种族如何在胃IM的发病机制中发挥作用， 通过我们的多机构联盟， （辛辛那提儿童医院、哥伦比亚大学和波多黎各大学）。我们将检验这个假设 细胞自主和非细胞自主机制是胃IM、异型增生和 目的1：确定肿瘤的分子基础， 使用诱导型多能干细胞（iPSC）的胃IM;目的2.为了阐明TP 53突变和 炎性信号有助于IM的起始和/或向发育异常和癌症的进展。 基因表达，转录调控和染色质可及性的表征将是非常宝贵的， 鉴定预防和/或治疗胃IM/发育不良的假定靶点。

PROGRAM SUMMARY Gastric cancer or GC (inclusive of gastroesophageal junction cancers) is the 5th most frequently diagnosed cancer globally. Significant variability in gastric cancer incidence and mortality has been reported between racial/ethnic groups. In the U.S., non-Hispanic Blacks (NHB), Hispanics (USH), and non-Hispanic Asian or Pacific Islander (NHAPI) are more commonly diagnosed with gastric cancer and have higher mortality compared to Non-Hispanic Whites (NHW). Intestinal metaplasia (IM) is a key precursor to GC with an intermediate stage of dysplasia. Gastric IM tends to be present at the antrum-corpus junction, particularly at the incisura angularis; gastric IM can also arise in the cardia. Factors that contribute to the development of gastric IM include bile reflux cigarette-smoking, alcohol, high salt intake, and H. pylori infection. A hallmark of IM in both the stomach and the esophagus (=Barrett’s esophagus) is the change of cellular identity to a columnar intestinal type of epithelium, suggesting that IM has shared mechanisms across these two organs. Several key transcription factors like CDX2 are functionally required to initiate IM, perhaps in concert with other factors and involving epigenetic reprogramming. The main goal of our proposed studies is to resolve fundamental gaps in the field (1) How does gastric IM arise? (2) Is there a common molecular pathway initiating IM in the gastric cardia and antrum? (3) How do TP53 tumor suppressor gene mutations and inflammatory cues each contribute to the initiation of IM? We will employ complementary, innovative platforms inducible pluripotent stem cells (iPSC) models, 3D organoids from patients with gastric IM, and co-culture of these organoids with fibroblasts and immune cells to decipher how microenvironmental cues catalyze the transition from metaplasia to dysplasia and GEJ/gastric adenocarcinoma. We seek to understand how ethnicity may play a role in the pathogenesis of gastric IM as that might reveal new insights and address health care disparities through our multi-institutional consortium (Cincinnati Children’s Hospital, Columbia University, and University of Puerto Rico). We will test the hypothesis that cell autonomous and non-cell autonomous mechanisms underlie the formation of gastric IM, dysplasia, and carcinoma through the following interrelated Specific Aims: Aim 1: To identify the molecular basis of gastric IM using inducible pluripotent stem cells (iPSC); Aim 2. To elucidate how TP53 mutations and inflammatory cues contribute to the initiation of IM and/or the progression to dysplasia and cancer. Characterization of gene expression, transcriptional regulation, and chromatin accessibility will be invaluable to identify putative targets to prevent and/or treat gastric IM/dysplasia.