Drivers of gastric pre-neoplasia

胃肿瘤前期的驱动因素

• 批准号: 10212349
• 负责人: Eunyoung Choi
• 金额: $ 39.57万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212349
• 关键词: Address; Adenocarcinoma; Alleles; Automobile Driving; Biology; Cancer Etiology; Cancerous; Cell Lineage; Cells; Cessation of life; Chief Cell; Colon Carcinoma; Development; Doxycycline; Dysplasia; Event; Evolution; Family; Gastric Adenocarcinoma; Gastric Metaplasia; Genes; Genetic Transcription; Gland; Goals; Histologic; Human; In Vitro; Individual; Intestines; Intrinsic factor; Investigation; KRAS oncogenesis; Kinetics; Knowledge; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of pancreas; Metaplasia; Molecular; Mus; Oncogenic; Outcomes Research; Patients; Process; RNA; Role; Signal Pathway; Stomach; Tetanus Helper Peptide; Therapeutic Intervention; Time; Tissues; Transcriptional Regulation; Transgenic Mice; Up-Regulation; Zymogen Granules; base; carcinogenesis; carcinogenicity; design; driving force; gastric carcinogenesis; gastric pre-neoplasia; genomic locus; in vivo; insight; malignant stomach neoplasm; mouse model; new therapeutic target; novel; overexpression; pre-clinical; premalignant; preventive intervention; transcription factor; transdifferentiation

PROJECT SUMMARY / ABSTRACT Gastric cancer is one of the most common causes of cancer-related death worldwide. It develops in a sequential progression of a carcinogenic cascade from pre-cancerous metaplasia to cancerous dysplasia and adenocarcinoma. However, oncogenic drivers or master regulators which lead to carcinogenic transition between pre-cancerous and cancerous stages are uncertain. Previous investigations have noted that Kras activity is observed in up to 40% of patients with gastric cancer and have suggested that Ras activation in gastric cancer may promote the progression of metaplasia toward dysplasia and cancer. Our previous results described that Kras activation in chief cells can rapidly develop metaplasia and invasive metaplasia with dysplastic glands. These studies therefore imply that Kras activation might be a driving factor of gastric carcinogenesis and chief cells might be an origin of gastric cancer. However, there is a clear knowledge gap as to whether Kras activation is a critical oncogenic driver which controls the carcinogenic process of dysplasia to adenocarcinoma. Also, while roles of Sox transcription factor activation following the oncogenic Kras activation have been well-studied in other GI tract cancers, no studies have addressed whether such activities are important for metaplasia development or are associated with Ras activation in gastric carcinogenesis. We have therefore hypothesized that Kras activation is a driver of gastric carcinogenesis and metaplastic development and progression can be controlled by upregulation of Sox9 as a downstream effector of Kras signaling pathway. We propose two specific aims to elucidate a deeper understanding of cellular mechanisms and events of gastric carcinogenesis using a novel inducible driver mouse model, which is a stomach- and chief cell-specific driver mouse allele. First, we will define the oncogenic roles of Kras activation and the lineage contribution of active Kras-induced cells during gastric carcinogenesis. Second, we will assess functional roles of Sox9 transcription factor as a putative master regulator of metaplasia development and progression. Our proposed study will not only define the cells of origin for gastric cancer, but also determine the oncogenic potential and regulatory mechanisms of Kras activation during gastric cancer development. Consequently, our results from this proposed study would provide insights in pre-clinical information to design therapeutic interventions or to identify novel druggable targets by regulating transcriptional regulation of key factors in patients with gastric cancer.

项目摘要/摘要 胃癌是全球最常见的癌症相关死亡原因之一。它是在一种 从癌前化生到癌异型增生的致癌级联反应的序贯进展和 腺癌。然而，致癌驱动因素或掌握导致致癌转变的调控因素 癌症前期和癌症阶段之间的关系是不确定的。此前的调查发现，克拉斯 在高达40%的胃癌患者中观察到活动，并表明RAS激活在 胃癌可能促进化生向异型增生和癌的发展。我们之前的结果 描述了主细胞中Kras的激活可以迅速发展为化生和侵袭性化生 发育不良的腺体。因此，这些研究提示Kras的激活可能是胃病的一个驱动因素。 癌变和主细胞可能是胃癌的起源之一。然而，有一个明显的知识鸿沟 至于Kras激活是否是控制不典型增生致癌过程的关键致癌驱动因素 到腺癌。此外，虽然SOX转录因子在致癌Kras之后的激活作用 激活在其他胃肠道癌症中已经得到了很好的研究，还没有研究表明这种活动是否 在化生过程中起重要作用，或与RAS在胃癌发生中的激活有关。 因此，我们假设Kras的激活是胃癌发生和化生的驱动因素。 作为Kras下游效应因子的Sox9的上调可以控制发育和进展 信号通路。我们提出了两个具体的目标来阐明对细胞机制的更深层次的理解 以及使用一种新的可诱导驱动小鼠模型的胃癌发生事件，该模型是胃和 主要细胞特异性驱动鼠等位基因。首先，我们将定义Kras激活的致癌作用和 活性Kras诱导的细胞在胃癌发生过程中的谱系贡献。第二，我们将评估 Sox9转录因子作为化生发生和发展的主要调节因子的功能 进步。我们提议的研究不仅将确定胃癌的起源细胞，而且还将确定 Kras在胃癌发生发展过程中的致癌潜力及其调控机制。 因此，我们来自这项拟议研究的结果将为临床前信息的设计提供见解 治疗干预或通过调节KEY转录调控来确定新的可用药靶点 影响胃癌患者预后的因素。