Mechanisms underlying gastric intestinal metaplasia and carcinogenesis

计划摘要 胃癌或胃癌(包括胃食道结合部癌)是最常被诊断的第五大癌症 全球范围内的癌症。据报道，在胃癌发病率和死亡率之间存在显著差异 种族/民族群体。在美国，非西班牙裔黑人(NHB)、拉美裔美国人(USH)和非西班牙裔亚裔或 太平洋岛民(Nhapi)更常被诊断为胃癌，与之相比，死亡率更高 致非西班牙裔白人(Nhw)。肠上皮化生(IM)是胃癌的关键先兆，处于中间阶段 不典型增生。胃间质瘤多见于胃窦-体部交界处，尤其是切迹角部； 胃肠间质瘤也可发生在贲门。促进胃IM发展的因素包括胆汁反流 吸烟、酗酒、高盐摄入量和幽门螺杆菌感染。IM的一个特点是胃部和腹部 食道是一种柱状肠型上皮的细胞同一性的变化， 这表明IM在这两个器官中具有共同的机制。CDX2等几个关键转录因子 在功能上需要启动IM，可能与其他因素协同并涉及表观遗传 重新编程。我们提议的研究的主要目标是解决该领域的根本差距(1)如何 胃肠间质瘤的发生？(2)在胃门部和胃窦部是否有共同的分子通路启动肠化？(3) TP53抑癌基因突变和炎症信号如何各自促进IM的启动？ 我们将采用互补的创新平台可诱导多能干细胞(IPSC)模型，3D 来自胃IM患者的有机物，并将这些有机物与成纤维细胞和免疫细胞共培养以 破译微环境线索如何催化从化生到异型增生和GEJ/胃部的转变 腺癌。我们试图了解种族如何在胃肠炎的发病机制中发挥作用。 可能会揭示新的见解并通过我们的多机构联盟解决医疗保健差距 (辛辛那提儿童医院、哥伦比亚大学和波多黎各大学)。我们将检验这一假设 细胞自主性和非细胞自主性机制是胃IM、异型增生和 肿瘤通过下列相互关联的特定目标：目标1：确定肿瘤的分子基础 利用可诱导多能干细胞(IPSC)进行胃IM；目的2.阐明TP53突变和 炎性线索有助于IM的启动和/或向异型增生和癌症的进展。 基因表达、转录调控和染色质可及性的表征将对 确定预防和/或治疗胃IM/异型增生的可能靶点。

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.