Gastroesophageal junction stem cells as the origin of Barretts esophagus and cancer

项目摘要 Barrett‘s食管腺癌(BE)的发病率迅速上升 到目前为止，交界性胃癌在美国已经造成了严重的健康和经济负担， 这些疾病的有效治疗选择有限，部分原因是对 最初的化生和随后的肿瘤进展的分子机制。此应用程序，由 两个具有互补专业知识的PI寻求通过结合scRNA-测序分析来解决该问题， 创新的BE鼠标模型和器官模型。我们之前曾证明过，贲门祖细胞 细胞和移行基底细胞位于胃-食道交界处的移行区。 (GEJ)。然而，这些前体细胞在BE-异型增生-EAC进展中的作用尚不清楚。 此外，推动疾病进展的分子机制也是未知的。我们的初步数据 提示GEJ化生及其向EAC的进展涉及P53缺失促进的祖细胞可塑性， BE的一种早期遗传损害。此外，我们还发现Barrett的化生和EAC与 丛生细胞的丰富。因此，我们假设Barrett的化生和异型增生起源于GEJ 祖细胞，受P53突变和簇状细胞扩增的调节。三个具体目标是 为检验这一假说而制定的公式：目标1是确定BE化生的起源和演变 EGJ处的祖细胞。目的2是阐明P53突变促进BE的机制 目的3是阐明丛状细胞在BE发病和进展中的作用。把我们的联合 在小鼠遗传学、细胞生物学、染色质生物学和表观基因组学方面的专业知识，这项工作将为 对巴雷特化生及其恶变机制的机械论见解，提供 治疗这些疾病的新方法。

Project Summary The rapid increase in the incidence of Barrett’s esophagus (BE), its malignant form esophageal adenocarcinoma (EAC), and junctional gastric cancer has produced serious health and financial burdens in the U.S. Thus far, effective treatment options for these diseases are limited in part due to an incomplete understanding of the molecular mechanisms driving the initial metaplasia and subsequent neoplastic progression. This application, by two PIs with complementary expertise, seeks to address the issue through combining scRNA-sequencing analysis, innovative BE mouse models and organoid modeling. We previously demonstrated that gastric cardia progenitor cells and transitional basal cell (TBCs) contribute to BE in the transitional zone of the gastro-esophageal junction (GEJ). However, how these progenitor cells behave in BE-dysplasia-EAC progression remains unclear. Additionally, the molecular mechanism driving the disease progression is also unknown. Our preliminary data suggest GEJ metaplasia and its progression towards EAC involves progenitor plasticity facilitated by p53 loss, an early genetic lesion in BE. Furthermore, we found that Barrett’s metaplasia and EAC is associated with the enrichment of tuft cells. Therefore we hypothesize that Barrett’s metaplasia and dysplasia originate from GEJ progenitor cells, modulated by the presence of p53 mutation and tuft cell expansion. Three specific aims are formulated to test the hypothesis: Aim 1 is to determine the origins and evolution of BE metaplasia from progenitor cells at the EGJ. Aim 2 is to elucidate the mechanisms by which p53 mutation promotes BE progression, and Aim 3 is to clarify the role of tuft cells in BE pathogenesis and progression. Combining our joint expertise on mouse genetics, cell biology, chromatin biology and epigenomics, this work will provide novel mechanistic insights into the mechanisms underlying Barrett’s metaplasia and its malignant progression, offering new approaches to treat these diseases.