Cell plasticity in the origin of gastric carcinogenesis

胃癌起源中的细胞可塑性

• 批准号: 10505616
• 负责人: Eunyoung Choi
• 金额: $ 103.71万
• 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/10505616
• 关键词: ATAC-seq; Address; Adenocarcinoma; Alleles; Automobile Driving; CRISPR/Cas technology; Cancer Etiology; Cancerous; Cell Lineage; Cells; Cellular Structures; Cessation of life; Chief Cell; Chronic; Clonal Evolution; Derivation procedure; Dysplasia; Epigenetic Process; Evolution; Gastric Adenocarcinoma; Gastric Intraepithelial Neoplasia; Gastric Parietal Cells; Gene Activation; Gene Mutation; Genes; Genetic; Genetic Transcription; Goals; Heterogeneity; Human; In Vitro; Inflammation; Injury; Intestinal Intraepithelial Neoplasia; Intestinal Metaplasia; Lead; Lesion; Malignant Neoplasms; Metaplasia; Metaplastic Cell; Modeling; Molecular; Mucous Membrane; Mus; Mutation; Neoplastic Processes; Oncogenes; Oncogenic; Organoids; Pathway interactions; Patients; Phase; Population; Process; Production; Property; Recovery; Reporter; Role; Sampling; Signal Pathway; Source; Stomach; Therapeutic Intervention; Time; Transgenic Mice; cancer cell; cancer stem cell; carcinogenicity; cell type; epigenome; gastric cancer prevention; gastric carcinogenesis; gastric corpus; high risk; in vivo; malignant stomach neoplasm; mouse model; neoplastic; novel; precursor cell; premalignant; promoter; response; response to injury; single-cell RNA sequencing; spasmolytic polypeptide; stem cells; transcriptome; transdifferentiation; tumor progression

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.

抽象的 胃癌是全球癌症相关死亡的第四个主要原因，最常见的是发展 在从癌前化学上的致癌级联反应中，到发育不良和腺癌。 Metaplasias 首先是作为对损伤的反应，通过主要细胞转分解为痉挛性多肽 表达化生（SPEM）细胞。虽然这种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细胞的进展 肠上皮（IM）和发育不良。这种肿瘤过程也可能导致转录和 表观遗传变化和促进细胞谱系转化，其中产生了多种中间细胞类型 可以演变成癌细胞，包括在肿瘤期间可能出现的发育不良干细胞 过渡。此外，致癌基因突变负担可能与细胞谱系有关 发育不良干细胞转化和多样化向癌细胞。但是，尚不清楚是否 SPEM细胞的可塑性是导致细胞异质性和癌前变质的演变 不完整的IM，其患者进展到发育不良的风险更高，哪些机制是 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，显示功能性能和细胞谱系转换能力以驱动化生 发展为发育不良。我们的总体目标是定义控制细胞谱系的机制 将修复性SPEM细胞转换为不完整的IM和更多癌细胞谱系，这些谱系显示 更高的突变负担。为了直接解决这些问题，我们建立了体内转基因的小说 小鼠模型和从转基因小鼠胃衍生的体外化生或异型器官模型 诱导活跃的KRA或从人类患者样品中，具有化生或发育不良的样本。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解释的细胞群体 在化学进展过程中产生的关键转录和表观遗传变化。我们将追求三个 具体目的：首先，我们将评估粘膜恢复或肿瘤期间SPEM细胞的功能特性 粘膜损伤后进展。其次，我们将检查细胞谱系的调节机制 化学进展过程中的多样化和转换。第三，我们将研究分子机制 驱动细胞外线多样化和发育不良干细胞对腺癌的克隆进化。我们的研究 将定义临界过渡点，从而导致SPEM细胞的肿瘤转变为胃的起源 致癌作用。了解细胞可塑性中的调节机制和逆转这种能力 过渡可能导致治疗干预措施以预防胃癌。