Cell plasticity in the origin of gastric carcinogenesis

摘要 胃癌是全球癌症相关死亡的第四大原因，它最常见的发病方式是 在从癌前化生到不典型增生和腺癌的致癌级联中。化生藻类 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。虽然这一初始过程可能是可逆的，但致癌基因 激活或慢性炎症可以激活SPEM细胞的可塑性，从而促进SPEM细胞进展为 肠化生(IM)和异型增生。这种肿瘤过程也可能导致转录和 表观遗传变化，并激发细胞谱系转换，产生多种中间细胞类型 可以进化成癌细胞，包括在肿瘤发生过程中可能出现的发育不良干细胞 过渡。此外，致癌基因突变的负担可能与细胞谱系有关。 发育不良的干细胞向癌细胞的转化和多样化。然而，目前还不清楚是否 SPEM细胞的可塑性导致细胞异质性和癌前化生向 不完全IM，患者进展为异型增生的风险更高，机制是什么？ 参与致癌过程。因此，我们假设SPEM细胞是关键的胃癌。 前体细胞，显示功能特性和细胞谱系转换能力，以驱动化生 进展为发育不良。我们的首要目标是定义控制细胞谱系的机制 修复性的SPEM细胞转化为不完全的IM和更多的癌细胞系，表现为 更高的突变负担。为了直接解决这些问题，我们建立了新型的体内转基因 转基因小鼠胃的小鼠模型和体外化生或发育不良类器官模型 在活动性Kras诱导后，或从化生或异型增生的人类患者样本中提取。使用这些 新的模型，我们将评估关键的SPEM细胞谱系派生，并定义解释 化生进展过程中出现的关键转录和表观遗传变化。我们将追求三个目标 具体目标：首先，我们将评估黏膜恢复或肿瘤期间SPEM细胞的功能特性 粘膜损伤后的进展。第二，我们将研究细胞谱系的调节机制。 化生进展过程中的多样化和转化。第三，我们将研究分子机制 推动发育不良干细胞向腺癌的细胞谱系多样化和克隆性进化。我们的研究 将确定导致SPEM细胞肿瘤性转变的关键过渡点作为胃的起源 致癌。了解细胞可塑性的调节机制和逆转这种机制的能力 这种转变可能会导致采取治疗措施来预防胃癌。

ABSTRACT 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.