Epigenetic regulation of pancreatic cancer

胰腺癌的表观遗传调控

• 批准号: 8646377
• 负责人: Matthias Hebrok
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-03 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8646377
• 关键词: Ablation; Acinar Cell; Address; Adult; Benign; Cancer Etiology; Cells; Cessation of life; Chromatin Remodeling Factor; Clinical; Code; Collaborations; Cues; Data; Development; Diagnosis; Duct (organ) structure; Ductal; Early Diagnosis; Enzymes; Epigenetic Process; Epithelium; Gene Expression; Gene Targeting; Genes; Goals; Growth; Human; Intraepithelial Neoplasia; Knowledge; Lesion; Longevity; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Medicine; Metaplasia; Molecular; Molecular Analysis; Morphology; Mucinous; Mus; Neoplasms; Neoplastic Cell Transformation; Oncogenic; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pancreatic duct; Papillary; Physiological; Population; Process; Proteins; Regulation; Role; Sampling; Series; Specimen; Staging; Stem cells; Testing; Therapeutic Intervention; Transgenic Animals; Transgenic Mice; Transgenic Model; United States; Universities; Utah; base; cell type; chromatin remodeling; combat; human disease; insight; intraepithelial; mouse model; mutant; neoplastic; new therapeutic target; novel; novel diagnostics; novel marker; outcome forecast; overexpression; prevent; progenitor; public health relevance; response; tool; tumor; tumor initiation

Project Summary/Abstract Pancreatic adenocarcinoma (PDA) carries one of the most dismal prognoses in all of medicine and is currently the 4th leading cause of cancer death in the United States. Several subtypes of PDA have been identified that vary greatly with regard to their lethality. Preliminary studies presented in this proposal support the notion that diverse PDA subtypes form from distinct pancreas cell populations, including duct and acinar cells. Importantly, we have identified a specific gene coding for a chromatin remodeling enzyme that modulates the response to tumor-inducing cues in these different cell types. Elimination of the gene in duct cells of transgenic mice supports the development of morphological and molecular changes associated with the formation of the more benign PDA subtype. In contrast, the gene product is required for the development of the more aggressive form of PDA in acinar cells. Thus, we have identified a novel regulator of PDA subtype formation. We propose to test how the loss of the chromatin remodeler changes the differentiation state of pancreatic duct cells and makes them prone to develop the more benign subset of pancreatic cancer. Conversely, we present an experimental strategy to test how the loss of this gene prevents formation of the more aggressive form of PDA from acinar cells. We have already identified potential target genes for both the aggressive and more benign subtypes and will test whether manipulation of these factors initiates or prevents the early stages of benign and aggressive tumor formation. Finally, we are focusing on one particular target that we recently characterized to be essential for the development of the aggressive form. In this application we will test whether changes in gene expression of that factor can interfere with the development of the PDA subtypes. Throughout the proposal, we are using state of the art transgenic animals and molecular tools to address the questions outlined above. Furthermore, we have established close collaborations with clinical colleagues both at UCSF and at the University of Utah who will provide us with specimen of human cancer samples to test and verify that new factors identified in our mouse models have relevance to the human disease. It is our goal to identify both novel diagnostic markers that can be used for the early detection of the subsets of PDA as well as novel therapeutic targets that could be exploited to attack the cancer ones it has formed. These studies fulfill a critical gap as our knowledge about the formation and molecular mechanisms underlying the development of the more benign form of pancreatic cancer is limited. By understanding how the more benign cancer forms and how this differs from the formation of the aggressive form, we hope to gain critical insights into how one can manipulate the aggressive tumors to reduce it growth potential.

项目总结/摘要 胰腺癌（PDA）是所有医学中最令人沮丧的疾病之一， 是美国癌症死亡的第四大原因。已经鉴定出PDA的几种亚型， 它们的致命性差别很大。该提案中提出的初步研究支持以下观点： 不同的PDA亚型由不同的胰腺细胞群形成，包括导管和腺泡细胞。 重要的是，我们已经确定了一个特定的基因编码的染色质重塑酶，调节 对这些不同细胞类型的肿瘤诱导信号的反应。消除导管细胞中的基因， 转基因小鼠支持发展的形态和分子变化与 形成更良性的PDA亚型。相反，基因产物是发育所必需的。 在腺泡细胞中更具有侵袭性的PDA形式。因此，我们已经确定了一个新的调节PDA亚型 阵 我们打算检测染色质重塑物的丢失如何改变胰管的分化状态 细胞，使他们更容易发展为胰腺癌的良性亚型。相反，我们提出 一种实验策略来测试这种基因的缺失如何阻止更具侵略性的形式的形成， 腺泡细胞的PDA。我们已经确定了潜在的靶基因， 良性亚型，并将测试是否操纵这些因素启动或防止早期阶段的 良性和侵袭性肿瘤形成。最后，我们正集中于一个特定的目标， 以侵略性形式的发展为特征的。在这个应用程序中，我们将测试 该因子基因表达的变化是否会干扰PDA亚型的发展。 在整个提案中，我们正在使用最先进的转基因动物和分子工具来解决 上述问题。此外，我们还与临床同事建立了密切的合作关系， 在加州大学旧金山分校和犹他州大学，他们将为我们提供人类癌症样本进行测试， 验证在我们的小鼠模型中发现的新因素与人类疾病有关。我们的目标是 确定可用于早期检测PDA子集的新型诊断标记物以及 新的治疗靶点，可以用来攻击它所形成的癌症。 这些研究填补了一个关键的空白，因为我们的知识的形成和分子机制的基础 良性胰腺癌的发展受到限制。通过了解越多的 良性癌症的形成以及这与侵袭性癌症的形成有何不同，我们希望获得关键的 深入了解如何操纵侵袭性肿瘤以降低其生长潜力。