Common Stem Cell of Origin for Junctional and Gastric Adenocarcinoma

交界腺癌和胃腺癌的共同起源干细胞

• 批准号: 10705117
• 负责人: Jaffer A. Ajani
• 金额: $ 91.67万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705117
• 关键词: Adult; Agreement; B-Lymphocytes; Barrett Esophagus; Biology; Cancer Model; Categories; Cell surface; Cells; Chronic; Clinical; Clone Cells; Cloning; Data; Data Set; Detection; Disease; Distal; Drug Combinations; Drug Screening; Dysplasia; Early Diagnosis; Embryonic Development; Engineering; Esophageal Adenocarcinoma; Esophageal mucous membrane; Esophagogastric Junction; Esophagus; Evolution; Expression Profiling; Gastric Adenocarcinoma; Gastric and esophageal adenocarcinomas; Gastric mucosa; Gene Expression; Genes; Genetic; Gland; Histologic; Homeobox; Human; In Vitro; Intestinal Metaplasia; Intestines; Kinetics; Knockout Mice; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of esophagus; Methods; Modeling; Molecular; Molecular Profiling; Mucous Membrane; Mus; Mutation; Natural History; Oncogenes; Oncogenic; Oncologist; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phylogenetic Analysis; Population; Proliferating; Proteomics; Resolution; Site; Sorting; Source; Specialist; Stomach; Technology; Therapeutic; Tissues; Xenograft procedure; advanced disease; cancer genetics; cancer genomics; carcinogenesis; cell type; drug development; drug discovery; gastric intestinal metaplasia; gastrointestinal; high-throughput drug screening; human fetal cells; human stem cells; in vivo; inhibitor; insight; malignant stomach neoplasm; mouse model; premalignant; prevent; prospective; small molecule; spelling; stem cell population; stem cells; therapeutic target; transcription factor; tumor; upper gastrointestinal cancer; whole genome

SUMMARY Despite their emergence from distal esophagus and distal stomach, respectively, esophageal adenocarcinoma (EAC) and intestinal gastric cancer (iGC) share the natural histories and molecule genetics of a single disease. Historically, EAC and iGC were among the first cancers to be linked to the prior presence of discrete, pre- cancerous lesions that can progress to dysplasia and then invasive disease over a two-decade interval. In both cases the earliest precancerous lesion was an odd "intestinal metaplasia; IM" known as "Barrett's esophagus (BE)" for EAC and "gastric intestinal metaplasia (GIM)" for iGC. These common evolutionary features have been extended by cancer genetics breakthroughs that place EAC and iGC into single cluster distinct from other gastric and esophageal cancers. While it was widely anticipated that advances in endoscopic and ablative technologies applied to precursor lesions would spell the end of EAC and iGC, rates of EAC and iGC have not appreciably decreased and most patients still present with advanced disease and poor five-year survival. This dire clinical reality has predicated a broad effort to understand the cell-of-origin of these diseases, their earliest emergence towards pathology, as well as their detection and pharmaceutical elimination. A highly collaborative team consisting of upper gastrointestinal oncologists, stem cell and molecular biologists, experts in murine cancer modeling, and proteomics specialists has employed advanced stem cell cloning technologies to capture patient-matched stem cells in each of the successive lesions in patients with EAC and iGC. In addition to the high-resolution phylogenetics afforded by these stem cells, this analysis has revealed the BE and GIM stem cells are indistinguishable at the level of whole genome expression profiling down to the level of homeotic transcription factors that define cellular identity. Common cell surface markers of BE and GIM stem cells identify a discrete population of cells at both the gastroesophageal (GE) junction and in the distal stomach of normal mice which we hypothesize are the intrinsic source of the IM for EAC and iGC respectively. These markers have also enabled the cloning of the corresponding site-specific stem cells, which we find to be indistinguishable gene expression profiles and to be committed to IM upon in vitro differentiation. In three aims, we will 1) use similar methods to clone the intrinsic IM stem cells from human fetal and adult GE junctions and gastric mucosa; 2) engineer mouse models for conditional expression of oncogenic factors in intrinsic IM cells; and 3) identify small molecules that selectively target intrinsic IM stem cells as leads for therapeutics to prevent EAC and iGC. We anticipate that the studies proposed herein will provide new insights into the biology and origin of these remarkably similar and widespread cancers, provide datasets essential for prospective early detection screens, and yield highly selective therapeutics that eliminate the nascent lesions essential for the evolution of these cancers.

概括 尽管它们来自食管远端和胃远端，但食管腺癌的出现 （EAC）和肠胃癌（IGC）共享一种疾病的自然史和分子遗传学。 从历史上看，EAC和IGC是最早与先前存在的离散，预先存在有关的癌症之一 可以在两个十年的时间间隔内发展为发育异常，然后侵袭性疾病的癌变病变。在 两种情况最早的癌前病变都是一个奇怪的“肠道化生； IGC的EAC和“胃肠化生（GIM）”的食道（BE）。 特征已通过将EAC和IGC纳入单个集群的癌症遗传学突破扩展 与其他胃癌和食道癌不同。虽然广泛认为进步 应用于前体病变的内窥镜和烧蚀技术将拼写为EAC和IGC的结束，费率 EAC和IGC的尚未明显减少，大多数患者仍然患有晚期疾病， 五年生存差。这种可怕的临床现实已经为了解 这些疾病，最早的病理学出现，以及它们的检测和药物 消除。一个高度协作的团队，由上胃肠道肿瘤学家，干细​​胞和 分子生物学家，鼠类癌建模的专家和蛋白质组学专家已采用高级 干细胞克隆技术以捕获每个连续病变中患者匹配的干细胞 EAC和IGC患者。除了这些干细胞提供的高分辨率系统发育学之外， 分析表明，在整个基因组水平上，BE和GIM干细胞是无法区分的 表达分析至定义细胞身份的同源转录因子的水平。常见的 BE和GIM干细胞的细胞表面标记在两个 胃食管治（GE）结，在我们假设的正常小鼠的远端胃中 EAC和IGC的IM的固有来源。这些标记还启用了克隆 相应的位点特异性干细胞，我们认为这是无法区分的基因表达谱，并且要为 致力于IM进行体外分化。在三个目标中，我们将使用类似的方法克隆固有的 IM来自人类胎儿和成人GE连接和胃粘膜的干细胞； 2）工程师鼠标模型 内在IM细胞中致癌因子的条件表达； 3）识别有选择性的小分子 靶向固有的IM干细胞，作为预防EAC和IGC的治疗剂的铅。我们预计研究 本文提出的将提供有关这些非常相似的生物学和起源的新见解，并且 广泛的癌症，为预期的早期检测屏幕提供必不可少的数据集并高度产生 选择性疗法消除了这些癌症进化至关重要的新生病变。