TGF-beta Signaling in Pancreatic Cancer Progression

摘要 胰腺癌几乎是一种致命的疾病。今年在美国，估计有 37680名患者将被诊断为胰腺癌，34290名患者将死于他们的疾病。 与大量数据显示基因或表观遗传变化与 胰腺癌发生，与胰腺特异和一致相关的遗传事件 癌症转移的定义还不是很清楚。然而，这是癌症过程的最后阶段- 癌细胞不受控制地生长和/或扩散到其他器官--这最终是 对大多数与癌症相关的死亡负有责任。这一事实与人类特别相关 胰腺癌。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，这种疾病不适合手术治疗。 切除手术。专注于胰腺癌转移的研究有可能极大地扩大我们的 了解该病最致命的阶段，并确定新的治疗区域 干预。我们最近描述了胰腺癌失败的类型。 尸检参与者发现，DPC4基因的遗传失活与 尸检发现广泛的转移性失败。因此，我们提出了三个具体目标，以 了解转化生长因子-β通路在胰腺癌进展中的作用。首先，我们将 对匹配的原发灶和转移瘤进行高通量测序和拷贝数评估 来自48名接受过快速尸检的患者的组织，并使用这一史无前例的数据集 确定胰腺癌的转移基因。这个基因“分类器”将会是 在一组独立的早期胰腺癌患者组织中独立验证 结果已知。第二，我们将确定TP53和转化生长因子-β途径的协同作用 利用两种特征良好的小鼠模型研究胰腺癌发生和进展的变化 胰腺癌。第三，我们将使用从快速尸检中获得的特征良好的细胞系。 患者确定DPC4修复或DPC4基因敲除对经典型和 非典型性转化生长因子-β信号通路及其与侵袭和自发转移的关系 在活体内。这些发现将是重要的，因为它们将导致治疗的改进 根据胰腺癌患者预期的失败模式进行治疗，包括 这种疾病的新的合理治疗方法的开发。

ABSTRACT 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-¿ 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-¿ 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 noncanonical TGF-¿ 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.