Initiation of Diffuse and Intestinal Non-Cardia Gastric Cancer

摘要 胃癌（GC）是全球癌症死亡的第三大原因，其特征在于 组织学和分子标准。两种最常见的形式包括扩散GC（DGC）和 肠GC（IGC）。每种类型的GC都与不同肿瘤的早期失活有关 抑制子，CDH 1（编码E-cadherin）用于DGC，p53用于IGC。除了基因变化， 胃癌的发展是由环境因素，特别是螺杆菌， 感染和暴露于饮食硝酸盐。我们认为，解决两个基本问题 在胃癌领域：定义细胞的起源和定义不同的介质， 鉴于它们之间的相互关联性，这些问题应一并处理。我们将评估 基因和环境因素在胃癌发生发展中相互作用 在小鼠模型中，我们可以选择性地靶向胃上皮中的关键肿瘤抑制因子， 配合相关曝光。然后，我们将深入研究组织与组合， 多组学单细胞技术实现基因表达和染色质的双重分析 在单个细胞中的可访问性和随后使用的空间转录组学工具， 在空间上绘制单个细胞类型的特征，以细化这些改变的细胞的细胞起源， 类型为了明确两类胃癌的细胞起源，我们 将评估综合多组学和空间分析，以确定细胞内的变化， 这些改变的表型的程序和候选介质。此外，我们将探讨如何 胃微环境的共同进化变化可能伴随或促进细胞的 癌前病变我们将更好地定义环境暴露的相互作用， 胃肿瘤的发生，并研究所产生的早期突变与环境的相互作用 因素，测试我们的假设，这种相互作用调节胃细胞和 微环境利用我们的细胞和空间分析，我们将生成一个地图， 微环境显示疾病在其空间背景下的发展，这也将 成为未来研究的资源。为了将我们在小鼠中的发现推广到人类，我们将执行 人和小鼠衍生类器官的单细胞多组分析，并扩展我们现有的 人类胃肠道的单细胞图谱。随后，我们将对 候选进展介质，评价胃上皮细胞固有的两种特征 和那些从微环境中出现的。这些研究都将解决长期存在的问题。 关于胃癌起源的争论以及确定预防癌症的新靶点 发展

ABSTRACT Gastric cancer (GC), the third leading cause of cancer death worldwide, is characterized both by histologic and molecular criteria. The two most common forms include Diffuse GC (DGC) and Intestinal GC (IGC). Each class of GC is associated with early inactivation of a distinct tumor suppressor, CDH1 (encoding E-cadherin) for DGC and p53 for IGC. Beyond genetic changes, gastric cancer development is promoted by environmental factors, specifically Helicobacter infection and exposure to dietary nitrates. We posit that addressing two fundamental questions in the gastric cancer field: defining the cells-of-origin and defining the distinct mediators of progression, should be addressed together given their interconnectedness. We will evaluate the interplay of genetic and environmental precipitants to gastric cancer using novel engineered mouse models where we can selectively target key tumor suppressors in the gastric epithelium in concert with relevant exposures. We will then deeply interrogate tissues with the combination of multi-omic single cell technologies enabling dual analysis of gene expression and chromatin accessibility in individual cells and the subsequent use of spatial transcriptomic tools allowing us to map features of individual cell types spatially to refine the cellular origins of these altered cell types. In concert to defining cellular origins of the two primary classes of gastric cancer, our integrated multi-omic and spatial analyses will be evaluated to define changes in cellular programs and candidate mediators of these altered phenotypes. In addition, we will explore how coevolving changes in the gastric microenvironment may accompany or promote the cell’s precancerous transformation. We will better define the interaction of environmental exposures in gastric tumorigenesis and investigate interactions of resulting early mutations with environmental factors, testing our hypothesis that this interaction modulates both gastric cells and microenvironment. Utilizing our cellular and spatial profiling, we will generate a map of the microenvironment showing the development of the disease in its spatial context, which will also be a resource for future studies. To generalize our findings in the mouse to human, we will perform single cell multi-ome analysis of human and mouse derived organoids and expand our existing single cell atlas of the human GI tract. Subsequently, we will perform functional validation of candidate mediators of progression, evaluating both features intrinsic to gastric epithelial cells and those emerging from the microenvironment. These studies will both address longstanding debates over origins of gastric cancers as well as define new targets to prevent cancer development.