TGF-beta Signaling in Pancreatic Cancer Progression

摘要 胰腺癌是一种几乎一律致命的疾病。今年在美国， 37，680名患者将被诊断患有胰腺癌，34，290名患者将死于这种疾病。 与大量的数据表明与以下疾病相关的遗传或表观遗传改变相反， 胰腺癌发生，与胰腺癌特异性和一致性相关的遗传事件， 癌症转移还没有被很好地定义。然而，正是癌症过程的最后阶段- 不受控制的生长和/或癌细胞扩散到其他器官-这最终是 导致了大多数癌症相关的死亡。这一事实对人类特别重要。 胰腺癌与这种疾病相关的令人沮丧的预后主要是由于以下事实， 大多数患者在疾病的晚期被诊断， 切除术关注胰腺癌转移的研究有可能极大地扩展我们的研究领域。 了解这种疾病的最致命阶段，并确定新的治疗领域 干预我们最近的特点是胰腺癌失败的模式，在快速 尸检参与者，发现DPC 4基因的遗传失活与 尸检时发现转移失败因此，我们提出三个具体目标， 了解TGF-β通路对胰腺癌进展的贡献。一是 对匹配的原发性和转移性肿瘤进行高通量测序和拷贝数评估 来自48名接受快速尸检的患者的组织，并使用这一前所未有的数据集， 确定胰腺癌的促转移基因型。这种基因型“分类器”将是 在来自患者的独立的一组早期胰腺癌组织中独立验证 已知的结果。其次，我们将确定TP 53和TGF-β通路的协同作用， 使用两种良好表征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，以确定DPC 4恢复或DPC 4敲除对典型和 非经典TGF-β通路信号转导及其与侵袭和自发转移的关系 in vivo.这些发现将是重要的，因为它们将导致治疗的改善。 根据预期的失败模式管理胰腺癌患者，包括 为这种疾病开发新的合理疗法。

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.