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

• 批准号: 9912118
• 负责人: RAYMOND J. MACDONALD
• 金额: $ 32.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912118
• 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 Epithelial Cell; Epidermal Growth Factor Receptor; Gene Expression; 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; 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; mouse genetics; mutant; novel; pancreatic cancer cells; pancreatic tumorigenesis; premalignant; preservation; prevent; programs; public health relevance; therapeutic target; transcription factor; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic

 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（由申请人提供）：尽管细胞分化的启动和维持经常被称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的或假设的。在胰腺导管腺癌（PDAC）的情况下，本申请的PI已经鉴定了构成分化和肿瘤抑制之间的分子联系的转录因子网络。这个网络的核心是bHLH转录因子PTF 1A，它是分化的外分泌腺泡细胞中基因表达的主要调节因子。我们和其他人已经表明，虽然PDAC及其癌前PanIN前体病变表达导管细胞的标志物，它们在小鼠中是由分化的腺泡细胞而不是导管中的KRAS癌基因突变激活引起的。肿瘤起始的第一个限速步骤是腺泡导管重编程，由KRAS和包括EGFR在内的协同信号下调PTF 1网络介导。我们假设PTF 1网络活性决定了致癌KRAS的细胞和临床效应：当PTF 1活跃时，即使在突变KRAS存在的情况下，腺泡细胞也保持正常分化，癌症被抑制;相比之下，PTF 1下调在细胞水平释放致癌KRAS，产生侵袭性，致死性癌。使用复杂的小鼠遗传模型和新的患者来源的人PDAC细胞系的组合，在获得临床样本的支持下，我们将在三个目标中解决该假设的机制和翻译方面：（1）确定PTF 1A是否是抑制PanIN向PDAC进展所必需和充分的，（2）确定PTF 1A是否通过抑制肿瘤促进性EGFR-SOX 9信号传导轴来抑制PDAC起始，和（3）确定PTF 1网络在正常人胰腺和人胰腺癌细胞中的作用。这些目标将通过两个PI实验室开发的尖端遗传学，基因组学和生物信息学方法来实现，他们的研究计划提供了胰腺癌和胰腺转录调控方面的互补专业知识。总之，这些研究将解决分化作为胰腺癌治疗靶点的基础和临床相关性。