An epigenetic switch controlling pancreatic cancer susceptibility

控制胰腺癌易感性的表观遗传开关

基本信息

批准号：
8575919
负责人：
Lewis C Murtaugh
金额：
$ 20.89万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8575919
关键词：
Acinar Cell Address Adult Affect Animal Model Applications Grants Attention Cell physiology Cells DNA Binding Data Development Diagnosis Disease Down-Regulation Duct (organ) structure Ductal Elements Epigenetic Process Etiology Event Factor X Gene Expression Regulation Gene Mutation Gene Targeting Genes Genetic Genome Homeostasis Intervention KRAS2 gene Lesion Malignant Neoplasms Malignant neoplasm of pancreas Medicine Modeling Molecular Mus Mutation Nature Normal Cell Notch Signaling Pathway Oncogenes Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatitis Pharmaceutical Preparations Pharmacotherapy Phenotype Pilot Projects Predisposition Proteins Regulation Repression Research Signal Pathway Signal Transduction Site Somatic Mutation Stimulus Test Result Testing Tumor Suppression Work base cancer cell cancer initiation cell transformation chromatin immunoprecipitation chromatin remodeling genetic risk factor mouse model mutant novel pancreatic neoplasm prevent programs protein function public health relevance research study restoration transcription factor tumor tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Although activating mutations of the KRAS oncogene are ubiquitous in pancreatic ductal adenocarcinoma (PDAC) and its earliest precursor lesions, pancreatic intraepithelial neoplasia (PanIN), animal model studies indicate that this mutation alone is not sufficient to initiate transformation. Instead, additional stimuli synergize with RAS o promote transformation, and this synergy is first evident in ductal reprogramming of the exocrine acinar cells from which PDAC arises. We hypothesize that the epigenetic program sustaining acinar differentiation constitutes as a novel tumor suppressive mechanism in these cells, and that mutual inhibitory interactions of acinar differentiation regulators with the RAS signaling pathway create a bistable switch between normal and transformed cell phenotypes. In particular, we propose that positive autoregulation of the transcription factor Ptf1a, a master regulator of acinar differentiation, is targeted for inhibition during PDAC initiation, and that restoration of its activity could restore transformed cells to a quiescent and differentiated state We will test this hypothesis in a mouse PDAC model, based on Cre- dependent expression of oncogenic KrasG12D in adult acinar cells, where we have discovered that genetic loss of Ptf1a dramatically enhances transformation. We propose two specific aims in this pilot study, combining hypothesis-driven and discovery-focused approaches: (1) determine whether Ptf1a downregulation is necessary and sufficient for RAS transformation of adult acinar cells; (2) identify potential epigenetic mechanisms for cross-inhibitory interactions of Ptf1a function and RAS signaling. These experiments take advantage of the PI and co-PI's expertise in mouse PDAC models and acinar gene regulation, and address a novel and potentially targetable mechanism for tumor initiation in this currently intractable disease.

描述（由申请人提供）：尽管 KRAS 癌基因的激活突变在胰腺导管腺癌 (PDAC) 及其最早的前驱病变胰腺上皮内瘤变 (PanIN) 中普遍存在，但动物模型研究表明，仅此突变不足以启动转化。相反，额外的刺激与 RAS 协同作用，促进转化，这种协同作用首先在产生 PDAC 的外分泌腺泡细胞的导管重编程中表现出来。我们假设维持腺泡分化的表观遗传程序构成了这些细胞中的一种新型肿瘤抑制机制，并且腺泡分化调节剂与 RAS 信号通路的相互抑制相互作用在正常细胞表型和转化细胞表型之间创建了双稳态转换。特别是，我们提出转录因子 Ptf1a（腺泡分化的主要调节因子）的正向自动调节是 PDAC 启动期间抑制的目标，并且其活性的恢复可以将转化细胞恢复到静止和分化状态我们将检验这一假设在小鼠 PDAC 模型中，基于成年腺泡细胞中致癌 KrasG12D 的 Cre 依赖性表达，我们发现 Ptf1a 的遗传缺失会显着增强转化。我们在这项试点研究中提出了两个具体目标，结合假设驱动和以发现为中心的方法：（1）确定 Ptf1a 下调对于成体腺泡细胞的 RAS 转化是否必要且充分； (2) 确定 Ptf1a 功能和 RAS 信号传导交叉抑制相互作用的潜在表观遗传机制。这些实验利用了 PI 和 co-PI 在小鼠 PDAC 模型和腺泡基因调控方面的专业知识，并提出了一种新的、潜在的可靶向机制，用于在这种目前棘手的疾病中引发肿瘤。