Hierarchy of oncogenic gene mutations in gastric carcinogenesis

胃癌发生中致癌基因突变的层次

• 批准号: 10831328
• 负责人: Eunyoung Choi
• 金额: $ 18.4万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10831328
• 关键词: Address; Adenocarcinoma; Automobile Driving; Cancer Etiology; Cancerous; Cell Lineage; Cells; Cessation of life; Chief Cell; Chronic; Clonal Evolution; Derivation procedure; Dysplasia; Epigenetic Process; Evolution; Gene Activation; Gene Mutation; Genetic Transcription; Goals; Heterogeneity; Human; In Vitro; Inflammation; Injury; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Metaplasia; Modeling; Molecular; Mucous Membrane; Mutation; Neoplastic Processes; Oncogenic; Organoids; Patients; Population; Process; Property; Recovery; Sampling; Stomach; Therapeutic Intervention; Transgenic Mice; carcinogenicity; cell type; gastric cancer prevention; gastric carcinogenesis; high risk; in vivo; interest; malignant stomach neoplasm; mouse model; neoplastic; novel; precursor cell; premalignant; response; response to injury; spasmolytic polypeptide; stem cells; transdifferentiation; tumor progression

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.

抽象的 该申请是为了响应特殊利益通知（NOSI）而提交 非CA-23-045。胃癌是全球与癌症相关死亡的第四个主要原因，它最多 通常在致癌级联反应中发展， 腺癌。 Metaplasias首先出现是作为对主要细胞转变为损伤的反应 痉挛性多肽表达化生（SPEM）细胞。虽然这个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细胞可塑性，从而促进SPEM 细胞向肠道化生（IM）和发育不良的进展。这个肿瘤过程也可能导致 转录和表观遗传变化，并促进细胞谱系转化，其中多个中间细胞 产生可以演变成癌细胞的类型，包括可能出现的发育不良干细胞 在肿瘤过渡期间。此外，致癌基因突变负担可能与 细胞谱系转化和发育不良干细胞向癌细胞的多样化。但是，不是 清除SPEM细胞可塑性是否负责细胞异质性和癌前的演变 Metaplasia不完整的IM，其患者进展到发育不良的风险更高，什么 机理参与致癌过程。因此，我们假设SPEM细胞是关键 胃癌前体细胞，这些细胞显示功能性能和细胞谱系转换能力 转化为发育不良的进展。我们的总体目标是定义控制电池的机制 修复性SPEM细胞向不完整的IM和更多癌细胞谱系的谱系转化，这些谱系 表现出更高的突变负担。为了直接解决这些问题，我们在体内建立了小说 转基因小鼠模型以及源自转基因的体外化生或异型器官模型 诱导活性KRA或从人类患者样品中的小鼠胃或具有化生的患者样品或 发育不良。使用这些新型模型，我们将评估关键SPEM细胞谱系推导并定义细胞 解释化学期间关键转录和表观遗传变化的人群 进展。我们将追求三个具体目标：首先，我们将评估SPEM细胞的功能性能 在粘膜恢复或肿瘤损伤后肿瘤进展过程中。第二，我们将检查 细胞谱系多样化和转化过程中转化的调节机制。第三，我们 将研究驱动细胞衬的分子机制多样性和发育不良茎的克隆演化 细胞到腺癌。我们的研究将定义关键过渡点，从而导致肿瘤的转变 SPEM细胞作为胃癌的起源。对细胞中调节机制的理解 可塑性和扭转此类过渡的能力可能会导致治疗性干预措施以防止胃 癌症。