Suppression of pancreatic tumorigenesis by the PTF1 transcription factor network

PTF1转录因子网络抑制胰腺肿瘤发生

基本信息

批准号：
9251258
负责人：
RAYMOND J. MACDONALD
金额：
$ 32.07万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9251258
关键词：
Acinar Cell Address Adenocarcinoma Cell Adult BHLH Protein Binding Bioinformatics Carcinoma Cell Death Cell Line Cell physiology Cessation of life Chromatin Clinical Conflict (Psychology)Data Development Differentiation Therapy Differentiation and Growth Disease Down-Regulation Drug Targeting Duct (organ) structure Ductal Ductal Epithelial Cell Epidermal Growth Factor Receptor Gene Expression Gene Targeting Genes Genetic Genetic Models Genetic study Genomics Heart Homeostasis Human KRAS2 gene Knowledge Laboratories Lesion Life Light Link Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediating Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutation NR5A2 gene Neoplasms Oncogenes Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Patients Pharmacology Phenotype Predisposition Premalignant Proteins Regulator Genes Research Role Sampling Series Signal Transduction TP53 gene Testing Therapeutic Transcriptional Regulation Translations Tumor Suppression Tumorigenicity Work base cancer cell cancer cell differentiation clinical effect clinically relevant comparative gain of function inhibitor/antagonist loss of function mutant novel pancreatic cancer cells pancreatic tumorigenesis permissiveness prevent programs public health relevance therapeutic target transcription factor tumor tumor initiation tumor progression tumorigenesis tumorigenic

Acinar Cell Address Adenocarcinoma Cell Adult BHLH Protein Binding Bioinformatics Carcinoma Cell Death Cell Line Cell physiology Cessation of life Chromatin Clinical Conflict (Psychology)Data Development Differentiation Therapy Differentiation and Growth Disease Down-Regulation Drug Targeting Duct (organ) structure Ductal Ductal Epithelial Cell Epidermal Growth Factor Receptor Gene Expression Gene Targeting Genes Genetic Genetic Models Genetic study Genomics Heart Homeostasis Human KRAS2 gene Knowledge Laboratories Lesion Life Light Link Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Maps Mediating Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutation NR5A2 gene Neoplasms Oncogenes Oncogenic Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Patients Pharmacology Phenotype Predisposition Premalignant Proteins Regulator Genes Research Role Sampling Series Signal Transduction TP53 gene Testing Therapeutic Transcriptional Regulation Translations Tumor Suppression Tumorigenicity Work base cancer cell cancer cell differentiation clinical effect clinically relevant comparative gain of function inhibitor/antagonist loss of function mutant novel pancreatic cancer cells pancreatic tumorigenesis permissiveness prevent programs public health relevance therapeutic target transcription factor tumor tumor initiation tumor progression tumorigenesis tumorigenic

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项目摘要

DESCRIPTION (provided by applicant): Although the initiation and maintenance of cellular differentiation are often invoked as a brake to tumorigenesis, the actual mechanisms by which differentiation could suppress cancer are largely unknown or hypothetical. In the case of pancreatic ductal adenocarcinoma (PDAC), the PIs of this application have identified a transcription factor network that constitutes a molecular link between differentiation and tumor suppression. At the heart of this network is the bHLH transcription factor PTF1A, a master regulator of gene expression in differentiated exocrine acinar cells. We and others have shown that although PDAC and its precancerous PanIN precursor lesions express markers of duct cells, they arise in mice from mutational activation of the KRAS oncogene in differentiated acinar cells rather than ducts. The first rate-limiting step of tumor initiation is acinar-ductal reprogramming, mediated by downregulation of the PTF1 network by KRAS and cooperating signals including EGFR. We hypothesize that PTF1 network activity determines the cellular and clinical effects of oncogenic KRAS: when PTF1 is active, acinar cells maintain normal differentiation even in the presence of mutant KRAS, and cancer is suppressed; by contrast, PTF1 downregulation unleashes oncogenic KRAS at the cellular level to produce invasive, lethal carcinoma. Using a combination of sophisticated mouse genetic models and novel, patient-derived human PDAC cell lines, with support by access to clinical samples, we will address both the mechanistic and translational aspects of this hypothesis in three aims: (1) determine if PTF1A is necessary and sufficient to suppress PanIN-to- PDAC progression, (2) determine if PTF1A suppresses PDAC initiation through inhibition of a tumor- promoting EGFR-SOX9 signaling axis, and (3) establish the role of the PTF1 network in normal human pancreas and human pancreatic cancer cells. These aims will be addressed with cutting-edge genetic, genomic and bioinformatic approaches developed in the laboratories of the two PIs, whose research programs provide complementary expertise in pancreatic cancer and pancreatic transcriptional regulation. Together, these studies will address the basic and clinical relevance of differentiation as a therapeutic target in pancreatic cancer.

描述（通过应用提供）：尽管细胞分化的主动性和维持通常被作为肿瘤发生的制动器，但分化可以抑制癌症的实际机制在很大程度上是未知或假设的。在胰腺导管腺癌（PDAC）的情况下，该应用的PIS已经确定了一个转录因子网络，该网络构成了分化与肿瘤抑制之间的分子联系。该网络的核心是BHLH转录因子PTF1A，这是分化外分泌腺泡细胞中基因表达的主要调节剂。我们和其他人已经表明，尽管PDAC及其预科剂Panin前体病变表达了导管细胞的标志物，但它们来自分化腺泡细胞中Kras癌基因的突变激活小鼠，而不是管道。肿瘤起始的第一次限制步骤是通过KRAS下调PTF1网络介导的腺泡导管重编程，以及包括EGFR在内的信号。我们假设PTF1网络活性决定了致癌性KRAS的细胞和临床作用：当PTF1活跃时，即使存在突变体KRAS，腺泡细胞也会保持正常分化，并且抑制了癌症。相比之下，PTF1下调在细胞水平上释放了致癌性KRA，以产生侵入性致命癌。利用复杂的小鼠遗传模型和新颖的，患者衍生的人PDAC细胞系的组合，并通过获得临床样本的支持，我们将同时解决该假设的机械和翻译方面的三个目的：（1）确定PTF1A是否足以通过抑制PTF1A的PDAC PDAC PDAC PDAC PDAC PDAC PDAC PDAC PDAC PDAC PDAC PDAC PDAC启动，以确定PTF1A是否足以确定。 EGFR-SOX9信号轴，（3）在正常的人胰腺和人类胰腺癌细胞中确定了PTF1网络的作用。这些目标将通过在两个PI的实验室中开发的尖端遗传，基因组和生物信息学方法来解决，其研究计划在胰腺癌和胰腺转录调节方面提供了完整的专业知识。总之，这些研究将介绍分化作为胰腺癌治疗靶点的基本和临床相关性。