Epigenetic regulation of pancreatic cancer

胰腺癌的表观遗传调控

基本信息

批准号：
9215657
负责人：
Matthias Hebrok
金额：
$ 32.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/9215657
关键词：
ATP phosphohydrolase Ablation Acinar Cell Acinar Cell Carcinoma Address Adult Alpha Cell Benign Cancer Etiology Cells Cessation of life Chromatin Chromatin Remodeling Factor Clinical Code Collaborations Cues Data Development Diagnosis Duct (organ) structure Ductal Ductal Epithelial Cell Early Diagnosis Enzymes Epithelium Gene Expression Gene Targeting Genes Goals Growth Histologic Human 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 Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pancreatic duct Papillary Physiological Population Process Role Sampling Series Specimen Stem cells Supporting Cell Testing Therapeutic Intervention Transgenic Animals Transgenic Mice Transgenic Model United States Universities Utah base cancer subtypes cell type chromatin remodeling combat diagnostic biomarker epigenetic regulation gene product human disease insight intraepithelial mouse model mutant neoplastic new therapeutic target novel novel diagnostics novel marker overexpression pancreas development pancreatic neoplasm prevent progenitor public health relevance response targeted treatment tool tumor tumor initiation

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：胰腺腺癌（PDA）携带了所有医学中最令人沮丧的预后之一，目前是美国癌症死亡的第四主要原因。已经确定PDA的几种亚型在其杀伤力方面差异很大。该提案中介绍的初步研究支持了以下观点：从不同的胰腺细胞群体（包括管道和腺泡细胞）形成了不同的PDA亚型。重要的是，我们已经确定了编码染色质重塑酶的特定基因，该酶调节了这些不同细胞类型中对肿瘤诱导线索的反应。消除转基因小鼠管道细胞中的基因支持与形成更良性PDA亚型的形成相关的形态和分子变化的发展。相比之下，基因产物在腺泡细胞中开发PDA的更具侵略性形式是必需的。因此，我们已经确定了PDA亚型形成的新型调节剂。我们建议测试染色质重塑剂的损失如何改变胰管细胞的分化状态，并使它们容易发展胰腺癌的更良性子集。相反，我们提出了一种实验策略，以测试该基因的丧失如何阻止腺泡细胞中PDA的更具侵略性的形式。我们已经确定了侵略性和更良性亚型的潜在靶基因，并将测试这些因素的操纵是否引发或阻止良性和侵略性肿瘤形成的早期阶段。最后，我们专注于最近我们表明的一个特定目标，对于侵略性形式的发展至关重要。在此应用中，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，我们已经与UCSF和犹他大学建立了与临床同事的密切合作，他们将为我们提供人类癌症样品标本，以测试和验证我们的小鼠模型中确定的新因素是否与人类疾病相关。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可以利用的新型治疗靶标，可以攻击其形成的癌症。这些研究达到了关键的差距，因为我们对胰腺癌更良性形式的发展的形成和分子机制的了解是有限的。通过了解如何形成较良性的癌症以及这与侵略性形式的形成如何差异，我们希望能够对如何操纵侵袭性肿瘤来降低IT生长潜力的关键见解。