Hierarchy of oncogenic gene mutations in gastric carcinogenesis

摘要 本申请是对特别利益通知(NOSI)的回应，该通知被确认为 不是-CA-23-045。胃癌是全球与癌症相关的死亡的第四大原因，而且 通常在从癌前化生到不典型增生的致癌级联中发展，并 腺癌。化生最初是作为对损伤的反应，通过主细胞转分化为 痉挛多肽表达化生(SPEM)细胞。虽然这个初始过程可能是可逆的， 致癌基因激活或慢性炎症可激活SPEM细胞的可塑性，从而促进SPEM 细胞进展为肠化(IM)和异型增生。这种肿瘤过程也可能导致 转录和表观遗传的变化，并激发细胞谱系转换，其中多个中间细胞 产生的类型可以进化成癌细胞，包括可能出现的发育不良的干细胞 在肿瘤的转变过程中。此外，致癌基因突变的负担可能与 发育不良的干细胞向癌细胞的细胞谱系转化和多样化。然而，它并不是 明确SPEM细胞的可塑性是否与癌前病变的细胞异质性和演变有关 化生为不完全性IM，患者进展为异型增生的风险更高 致癌过程中涉及多种机制。因此，我们假设SPEM细胞是关键 胃癌前体细胞，表现出功能特性和细胞谱系转换能力，以驱动 化生进展为异型增生。我们的首要目标是定义控制细胞的机制 修复性SPEM细胞向不完全IM和更多癌细胞谱系的谱系转化，这 表现出更高的突变负担。为了直接解决这些问题，我们在体内建立了新的 转基因小鼠模型及转基因衍生的体外化生或发育不良类器官模型 活动性Kras诱导后的小鼠胃或来自人患者化生或 发育不良。使用这些新的模型，我们将评估关键的SPEM细胞谱系派生并定义细胞 在化生过程中引起关键转录和表观遗传变化的群体 进步。我们将追求三个具体目标：第一，我们将评估SPEM细胞的功能特性 在粘膜损伤后的粘膜恢复或肿瘤进展期间。第二，我们将审查 化生过程中细胞谱系多样化和转化的调控机制。第三，我们 将研究驱动发育不良干细胞细胞系多样化和克隆进化的分子机制 细胞转化为腺癌。我们的研究将定义导致肿瘤转变的关键过渡点 SPEM细胞作为胃癌发生的来源。对细胞内调控机制的认识 可塑性和逆转这种转变的能力可能导致预防胃病的治疗干预 癌症。

ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-23-045. Gastric cancer is the 4th leading cause of cancer-related death worldwide and it most commonly develops within a carcinogenic cascade from pre-cancerous metaplasia to dysplasia and adenocarcinoma. Metaplasias first arise as a response to injury through the chief cell transdifferentiation into spasmolytic polypeptide- expressing metaplasia (SPEM) cells. While this initial process is possibly reversible, oncogenic gene activation or chronic inflammation can activate SPEM cell plasticity, which promotes SPEM cell progression to intestinal metaplasia (IM) and dysplasia. This neoplastic process may also lead to transcriptional and epigenetic changes, and incite cell lineage conversion, where multiple intermediate cell types are produced that can evolve into cancerous cells, including dysplastic stem cells which may arise during the neoplastic transition. Furthermore, the oncogenic gene mutation burden may be associated with the cell lineage conversion and diversification of the dysplastic stem cells to cancerous cells. However, it is not clear whether the SPEM cell plasticity is responsible for the cell heterogeneity and evolution of pre-cancerous metaplasia to incomplete IM, which carries a higher risk of patient progression to dysplasia and what mechanisms are involved in the carcinogenic process. We therefore hypothesize that SPEM cells are key gastric cancer precursor cells, which display functional properties and cell lineage conversion capacity to drive metaplasia progression to dysplasia. Our overarching goal is to define mechanisms that control the cell lineage conversion of reparative SPEM cells towards incomplete IM and more cancerous cell lineages, which display a higher mutational burden. To address these questions directly, we have established novel in vivo transgenic mouse models and in vitro metaplastic or dysplastic organoid models derived from transgenic mouse stomachs following induction of active Kras or from human patient samples with metaplasia or dysplasia. Using these novel models, we will assess critical SPEM cell lineage derivation and define cell populations that account for the key transcriptional and epigenetic changes arising during metaplasia progression. We will pursue three specific aims: First we will assess functional properties of SPEM cells during mucosal recovery or neoplastic progression following mucosal injury. Second, we will examine regulatory mechanisms of cell lineage diversification and conversion during metaplasia progression. Third, we will investigate molecular mechanisms driving cell linage diversification and clonal evolution of dysplastic stem cells to adenocarcinoma. Our studies will define critical transition points which lead to neoplastic transitions for SPEM cells as the origin of gastric carcinogenesis. An understanding of regulatory mechanisms in cell plasticity and the ability to reverse such transitions could lead to therapeutic interventions to prevent gastric cancer.