TGF-beta Signaling in Pancreatic Cancer Progression

描述(申请人提供)：胰腺癌是一种几乎一致致命的疾病。今年在美国，估计有37680名患者将被诊断为胰腺癌，34290名患者将死于这种疾病。与大量显示与胰腺癌发生相关的基因或表观遗传学改变的数据相比，与胰腺癌转移相关的特异和一致的基因事件还没有被很好地定义。然而，正是癌症过程的这一最后阶段--癌细胞不受控制地生长和/或扩散到其他器官--最终导致了大多数与癌症有关的死亡。这一事实与人类胰腺癌特别相关。与这种疾病相关的悲观预后在很大程度上是由于大多数患者是在疾病的晚期被诊断出来的，而这种疾病不适合手术切除。集中于胰腺癌转移的研究有可能极大地扩大我们对这种疾病最致命阶段的理解，并确定新的治疗干预领域。我们最近在快速尸检参与者中描述了胰腺癌失败的模式，并发现DPC4基因的遗传失活与尸检中广泛的转移失败高度相关。因此，我们提出了三个特定的目标，以了解转化生长因子-b通路在胰腺癌进展中的作用。首先，我们将对48名接受过快速尸检的匹配的原发和转移组织进行高通量测序和拷贝数评估，并使用这一史无前例的数据集来识别胰腺癌的转移基因。这种基因“分类器”将在一组独立的早期胰腺癌组织中进行独立验证，这些组织来自已知结果的患者。其次，我们将利用两种特征良好的胰腺癌小鼠模型，确定TP53和转化生长因子-b途径改变在胰腺癌发生和发展中的协同作用。第三，我们将使用从快速尸检患者中获得的具有良好特性的细胞系来确定DPC4修复或DPC4基因敲除对典型和非典型转化生长因子-b通路信号的影响，以及它们与体内侵袭和自发转移的关系。这些发现将是重要的，因为它们将根据胰腺癌患者预期的失败模式，改进对他们的治疗管理，包括为这种疾病开发新的合理疗法。公共卫生相关性：胰腺癌是一种侵袭性疾病，预后很差，部分原因是大多数患者在疾病的晚期被诊断出来。在这个提案中，我们将研究控制生长和正常发育的最常见的途径之一，转化生长因子-b途径，以及它被改变以促进胰腺癌形成和扩散的机制。

DESCRIPTION (provided by applicant): Pancreatic cancer is an almost uniformly lethal disease. This year in the United States, an estimated 37,680 patients will be diagnosed with pancreatic cancer, and 34,290 patients will die of their disease. In contrast to the wealth of data demonstrating genetic or epigenetic alterations associated with pancreatic carcinogenesis, the genetic events specifically and consistently associated with pancreatic cancer metastasis have not been well defined. However, it is this final stage of the cancer process- the uncontrolled growth and/or dissemination of cancer cells to other organs-that is ultimately responsible for the majority of cancer-related deaths. This fact is of particular relevance to human pancreatic cancer. The dismal prognosis associated with this disease is largely due to the fact that most patients are diagnosed at an advanced stage of disease that is not amenable to surgical resection. Studies that focus on pancreatic cancer metastasis have the potential to greatly expand our understanding of the most lethal stage of this disease and identify novel areas for therapeutic intervention. We have recently characterized the patterns of pancreatic cancer failure in rapid autopsy participants and found that genetic inactivation of the DPC4 gene is highly correlated with widespread metastatic failure at autopsy. Thus, we propose three Specific Aims towards understanding the contribution of the TGF-b pathway to pancreatic cancer progression. First, we will perform high throughput sequencing and copy number evaluations of matched primary and metastatic tissues from 48 patients who have undergone rapid autopsy, and use this unprecedented dataset to identify the pro-metastatic genotype of pancreatic cancers. This genotype "classifier" will be independently validated in an independent set of early stage pancreatic cancer tissues from patients with known outcome. Second, we will determine the synergistic effects of TP53 and TGF-b pathway alterations in pancreatic carcinogenesis and progression using two well characterized mouse models of pancreatic cancer. Third, we will use well characterized cell lines derived from rapid autopsy patients to determine the effects of DPC4 restoration, or DPC4 knockout, on both canonical and non-canonical TGF-b pathway signaling and their relationship to invasion and spontaneous metastasis in vivo. These findings will be important because they will lead to improvements in therapeutic management of patients with pancreatic cancer based on their expected patterns of failure, including the development of novel rational therapies for this disease. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is an aggressive disease with a poor prognosis, in part because most patients are diagnosed at an advanced stage of disease. In this proposal we will study one of the most common pathways that control growth and normal development, the TGF-b pathway, and the mechanisms by which it is altered to promote pancreatic cancer formation and spread.