Epigenetic regulation of pancreatic cancer

描述（由申请人提供）：胰腺腺癌（PDA）是所有医学中预后最糟糕的疾病之一，目前是美国第四大癌症死亡原因。已经确定了PDA的几种亚型，它们的致死率差别很大。本提案中提出的初步研究支持不同的PDA亚型形成于不同的胰腺细胞群，包括导管细胞和腺泡细胞。重要的是，我们已经确定了一个编码染色质重塑酶的特定基因，该基因可以调节这些不同细胞类型对肿瘤诱导信号的反应。在转基因小鼠的导管细胞中消除该基因支持与良性PDA亚型形成相关的形态学和分子变化的发展。相反，这种基因产物是在腺泡细胞中形成更具侵袭性的PDA所必需的。因此，我们已经确定了一种新的PDA亚型形成调节因子。我们建议测试染色质重塑因子的缺失如何改变胰管细胞的分化状态，使它们更容易发展成良性的胰腺癌亚群。相反，我们提出了一种实验策略来测试该基因的缺失如何阻止腺泡细胞形成更具侵袭性的PDA。我们已经确定了侵袭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启动或阻止良性和侵袭性肿瘤形成的早期阶段。最后，我们将重点放在一个特定的目标上，我们最近将其定性为对攻击性形式的发展至关重要。在本应用中，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，我们与加州大学旧金山分校和犹他大学的临床同事建立了密切的合作关系，他们将为我们提供人类癌症样本样本，以测试和验证在我们的小鼠模型中发现的新因素与人类疾病有关。我们的目标是确定新的诊断标记物，可以用于PDA亚群的早期检测，以及新的治疗靶点，可以用来攻击它已经形成的癌症。这些研究填补了一个关键的空白，因为我们对良性胰腺癌的形成和分子机制的了解是有限的。通过了解良性肿瘤是如何形成的，以及它与恶性肿瘤的形成有何不同，我们希望获得关于如何操纵恶性肿瘤以降低其生长潜力的关键见解。

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.