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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：
9038164
负责人：
RAYMOND J. MACDONALD
金额：
$ 33.19万
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/9038164
关键词：
Acinar Cell Address Adenocarcinoma Cell Adult Binding Bioinformatics Carcinoma Cell Death Cell Line Cell physiology Cells Cessation of life Chromatin Clinical Conflict (Psychology)Data Development Differentiation Therapy Differentiation and Growth Disease Down-Regulation Drug Targeting Duct (organ) structure Ductal 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 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 prevent programs public health relevance therapeutic target transcription factor tumor tumor initiation tumor progression tumorigenesis tumorigenic

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.