Regulation of pancreatic ductal adenocarcinoma progression by Hnf4a

Hnf4a 对胰腺导管腺癌进展的调节

• 批准号: 9063112
• 负责人: Eric Lee Snyder
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-04 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9063112
• 关键词: Adenocarcinoma; Adenocarcinoma Cell; Adopted; Agonist; Anchorage-Independent Growth; Biological Process; Cell Line; Cells; Complementary DNA; Data; Development; Differentiation and Growth; Disease; Epithelial Cells; Exhibits; Future; Gastrointestinal tract structure; Genes; Genetic; Genetically Engineered Mouse; Goals; Growth; Health; Homeostasis; Human; Immunohistochemistry; In Situ; Inflammation; Investigation; Lesion; Liver; Lung Adenocarcinoma; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Metabolism; Modeling; Molecular; Mucinous; Mus; Neoplasms; Normal tissue morphology; Nuclear Receptors; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathway interactions; Play; Primitive foregut structure; RNA Interference; Regulation; Role; Specific qualifier value; Staging; Testing; Therapeutic; Tissues; Transcript; Well Differentiated Lesion; base; cancer type; design; gastrointestinal; knowledge translation; malignant state; mouse model; novel therapeutic intervention; novel therapeutics; overexpression; pancreatic neoplasm; preclinical study; response; small molecule; transcription factor; transcriptome sequencing; tumor; tumor initiation; tumor progression

 DESCRIPTION (provided by applicant): The molecular networks that specify cellular identity and suppress alternative cell fates are tightly regulated during normal tissue homeostasis but can become dramatically dysregulated during cancer progression. It has long been appreciated that tumor differentiation state often correlates with both intrinsic malignant potential and response to therapy. However, the master transcriptional regulators that control cellular identity in most cancer types remain to be elucidated. The long-term goal of this project is to determine how changes in cellular identity contribute to the progression of pancreatic ductal adenocarcinoma (PDAC). Pancreatic neoplasia adopts a foregut-like differentiation state that is distinct from normal pancreatic epithelial cells. We have observed that the differentiation state o pancreatic in situ neoplasia (PanIN) closely resembles that of mucinous lung adenocarcinoma, a type of lung cancer that also exhibits a foregut-like differentiation state. One of the foregut-associated transcripts expressed in both types of neoplasia is Hnf4α, a transcription factor that normally regulates the differentiation state of the gastrointestinal tract and liver. Using conditional murine genetics, we demonstrated that Hnf4α is a critical regulator of the growth and differentiation state of mucinous lung adenocarcinoma. In this proposal, we will test the hypothesis that Hnf4α regulates the differentiation state and malignant progression of pancreatic ductal adenocarcinoma using the following specific aims: (1) Determine the impact of Hnf4α loss on the differentiation and malignant progression of pancreatic ductal adenocarcinoma and (2) Characterize the mechanisms by which Hnf4α regulates the growth and differentiation state of pancreatic ductal adenocarcinoma.

 描述(由申请人提供)：指定细胞身份和抑制可供选择的细胞命运的分子网络在正常组织动态平衡期间受到严格调控，但在癌症进展过程中可能变得严重失调。长期以来，人们一直认为肿瘤分化状态往往与固有的恶性潜能和对治疗的反应有关。然而，在大多数癌症类型中控制细胞特性的主要转录调控因子仍有待阐明。该项目的长期目标是确定细胞特性的变化如何有助于胰腺导管腺癌(PDAC)的进展。胰腺肿瘤呈现一种不同于正常胰腺上皮细胞的前肠样分化状态。我们观察到胰腺原位瘤(Panin)的分化状态与粘液性肺腺癌非常相似，粘液性肺腺癌是一种也表现出前肠样分化状态的肺癌。在两种类型的肿瘤中表达的前肠相关转录本之一是HNF4α，这是一种转录因子，通常调节胃肠道和肝脏的分化状态。利用条件小鼠遗传学方法，我们证明了HNF4α是粘液性肺腺癌生长和分化状态的关键调节因子。在本研究中，我们将从以下几个方面对HNF4α调控胰腺癌分化状态和恶性进展的假说进行验证：(1)确定HNF4α缺失对胰腺癌分化和恶性进展的影响；(2)研究HNF4α调控胰腺导管腺癌生长和分化状态的机制。