Mechanisms underlying gastric intestinal metaplasia and carcinogenesis

胃肠化生和癌变的机制

• 批准号: 10707301
• 负责人: MARCIA Roxana CRUZ-CORREA
• 金额: $ 89.99万
• 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: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707301
• 关键词: 3-Dimensional; Address; Alcohols; American Cancer Society; Asian; Autologous; Barrett Esophagus; Bile Acids; Bile Reflux; Biological Models; Biopsy; Black Populations; CDX2 gene; Carcinoma; Cells; ChIP-seq; Chromatin; Coculture Techniques; Cues; Development; Diagnosis; Dietary Factors; Dysplasia; Early Diagnosis; East Asian; Epigenetic Process; Epithelial Cells; Epithelium; Esophagogastric Junction; Esophagus; Ethnic Origin; Ethnic Population; Fibroblasts; Fostering; Fundus; Gastric Adenocarcinoma; Gastric mucosa; Gene Expression; Gene Mutation; Genetic; Genetic Transcription; Goals; Helicobacter Infections; High Prevalence; Hispanic Populations; Human; Immune; Incidence; Individual; Inflammation; Inflammatory; Institution; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Intestinal Mucosa; Intestines; Malignant Neoplasms; Mediating; Metaplasia; Molecular; Mus; Mutation; Neoplasms; New York City; Not Hispanic or Latino; Organ; Organoids; Outcome; Pacific Islander; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Peripheral Blood Mononuclear Cell; Play; Population Heterogeneity; Prevention; Process; Property; Puerto Rico; Pyloric antrum; Reporting; Repression; Resolution; Role; SOX21 gene; Sampling; Stomach; TP53 gene; Testing; Tissue Model; Transcriptional Regulation; Tumor Suppressor Genes; Universities; Upper digestive tract structure; cancer diagnosis; cancer survival; carcinogenesis; carcinogenicity; cigarette smoking; ethnic difference; gastric carcinogenesis; gastric intestinal metaplasia; health care disparity; human data; human model; induced pluripotent stem cell; innovation; insight; loss of function; malignant stomach neoplasm; microorganism; mortality; mouse model; novel; prevent; programs; racial difference; racial population; risk stratification; salt intake; screening; single-cell RNA sequencing; spasmolytic polypeptide; stem cell model; stomach cardia; transcription factor; treatment strategy

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.

计划概要 胃癌或 GC（包括胃食管交界癌）是第五大最常诊断的癌症 据报道，全球范围内胃癌发病率和死亡率存在显着差异。 在美国，非西班牙裔黑人 (NHB)、西班牙裔 (USH) 和非西班牙裔亚裔或 与太平洋岛民 (NHAPI) 相比，太平洋岛民 (NHAPI) 更常被诊断出患有胃癌，且死亡率更高 非西班牙裔白人 (NHW) 肠化生 (IM) 是中间阶段 GC 的关键前兆。 胃部IM往往出现在胃窦-胃体交界处，特别是角切迹处； 胃部 IM 也可能出现在贲门部，导致胃部 IM 发生的因素包括胆汁反流。 吸烟、饮酒、高盐摄入和幽门螺杆菌感染是胃和胃部 IM 的标志。 食管（=巴雷特食管）是细胞身份改变为柱状肠上皮类型， 表明 IM 在这两个器官中具有相同的机制，例如 CDX2 等几个关键转录因子。 在功能上需要启动 IM，可能与其他因素一致并涉及表观遗传 我们提出的研究的主要目标是解决该领域的根本差距（1）如何进行。 胃 IM 出现吗？ (2) 胃贲门和胃窦是否存在启动 IM 的共同分子途径？ TP53 肿瘤抑制基因突变和炎症信号如何促进 IM 的启动？ 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发育异常和 GEJ/胃的转变 我们试图了解种族如何在胃 IM 的发病机制中发挥作用。 可能会通过我们的多机构联盟揭示新的见解并解决医疗保健差异 （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。 细胞自主和非细胞自主机制是胃 IM、发育不良和 癌症通过以下相互关联的具体目标实现： 目标 1：确定癌症的分子基础 使用诱导型多能干细胞 (iPSC) 进行胃 IM 目标 2. 阐明 TP53 突变如何与 炎症信号有助于引发 IM 和/或进展为不典型增生和癌症。 基因表达、转录调控和染色质可及性的表征对于 确定预防和/或治疗胃IM/发育不良的假定目标。

项目成果

RFX6 regulates human intestinal patterning and function upstream of PDX1.

RFX6 调节 PDX1 上游的人类肠道模式和功能。

• 发表时间: 2024-04-08
• 作者: Sanchez, J Guillermo;Rankin, Scott;Paul, Emily;McCauley, Heather A;Kechele, Daniel O;Enriquez, Jacob R;Jones, Nana;Greeley, Siri A W;Letourneau;Zorn, Aaron M;Krishnamurthy, Mansa;Wells, James M
• 通讯作者: Wells, James M