TGF-beta Signaling in Pancreatic Cancer Progression

描述（由申请人提供）：胰腺癌是一种几乎一致致命的疾病。今年在美国，估计将有37,680名患者被诊断患有胰腺癌，34290名患者将死于这种疾病。与证明遗传或表观遗传改变与胰腺癌发生相关的大量数据相反，与胰腺癌转移特异性和一致性相关的遗传事件尚未得到很好的定义。然而，正是癌症过程的最后阶段——癌细胞不受控制的生长和/或扩散到其他器官——才是导致大多数癌症相关死亡的最终原因。这一事实与人类胰腺癌特别相关。与这种疾病相关的惨淡预后主要是由于大多数患者被诊断为疾病的晚期，不适合手术切除。专注于胰腺癌转移的研究有可能极大地扩展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。我们最近描述了快速尸检参与者胰腺癌失败的模式，并发现DPC4基因的遗传失活与尸检中广泛的转移性失败高度相关。因此，我们提出了三个具体目标，以了解TGF-b途径对胰腺癌进展的贡献。首先，我们将对48例经过快速尸检的患者的匹配原发和转移组织进行高通量测序和拷贝数评估，并使用这个前所未有的数据集来确定胰腺癌的前转移基因型。这种基因型“分类器”将在一组独立的早期胰腺癌组织中进行独立验证，这些组织来自已知预后的患者。其次，我们将使用两种具有良好特征的胰腺癌小鼠模型来确定TP53和TGF-b通路改变在胰腺癌发生和进展中的协同作用。第三，我们将使用从快速尸检患者中提取的具有良好特征的细胞系来确定DPC4修复或DPC4敲除对典型和非典型TGF-b通路信号的影响及其与体内侵袭和自发转移的关系。这些发现将是重要的，因为它们将导致改善胰腺癌患者的治疗管理，基于他们预期的失败模式，包括开发新的合理的治疗方法。公共卫生相关性：胰腺癌是一种预后不良的侵袭性疾病，部分原因是大多数患者在疾病晚期被诊断出来。在本提案中，我们将研究控制生长和正常发育的最常见途径之一，TGF-b途径，以及其改变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.