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 胃癌是全球与癌症相关死亡的最常见原因之一。它在一个 致癌级联的顺序进展，从癌前化生型到癌性发育不全和 腺癌。但是，导致致癌过渡的致癌驱动器或主调节器 癌前和癌性阶段之间不确定。先前的调查指出，克拉斯 在多达40％的胃癌患者中观察到活性，并提出RAS激活 胃癌可能会促进化生症向发育不良和癌症的发展。我们以前的结果 描述的是，主要细胞中的KRAS激活可以迅速发展，并与 发育不良的腺体。因此，这些研究暗示KRAS激活可能是胃的驱动因素 癌变和主要细胞可能是胃癌的起源。但是，有一个明显的知识差距 关于KRAS激活是否是控制发育不良的致癌过程的关键致癌驱动器 到腺癌。另外，虽然在致癌性KRAS之后的Sox转录因子激活的角色 激活在其他胃肠道癌中得到了充分研究，尚无研究解决此类活动是否存在 对于化生发展至关重要，或与胃癌发生中的RAS激活有关。 因此，我们假设KRAS激活是胃癌发生的驱动力 开发和发展可以通过SOX9作为KRAS的下游效应子的上调来控制 信号通路。我们提出了两个特定的目的，以阐明对细胞机制的更深入的了解 以及使用新型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器鼠标等位基因。首先，我们将定义KRAS激活的致癌作用和 胃癌发生过程中活性KRAS诱导的细胞的谱系贡献。第二，我们将评估 Sox9转录因子的功能作用，是化学发展的推定主要调节剂 进展。我们提出的研究不仅将定义胃癌的起源细胞，而且还确定 胃癌发展过程中KRAS激活的致癌潜力和调节机制。 因此，我们从这项拟议的研究中的结果将提供有关设计前信息的见解 治疗干预措施或通过调节钥匙的转录调节来识别新型可毒靶 胃癌患者的因素。