ATDC Function in Human Pancreatic Adenocarcinoma

 描述（由申请人提供）：胰腺腺癌（PDA）是一种致命的疾病，其特征是诊断较晚，侵袭周围组织，早期转移。1A期疾病患者切除后的5年生存率为30%，这突出表明PDA在患者中早期转移，然而，驱动PDA早期转移的分子机制尚不清楚。我们最近发现，大多数人胰腺癌具有升高的共济失调-毛细血管扩张D组相关（ATDC）基因表达，并且ATDC通过Wnt途径激活和β-连环蛋白稳定在胰腺癌中具有致癌功能。使用新创建的胰腺癌基因工程小鼠模型，我们现在已经确定了ATDC在胰腺癌中以前未知的作用，其中ATDC在肿瘤发生的早期PanIN阶段上调，并且在致癌Kras的存在下，加速PanIN进展以及侵袭性和转移性肿瘤的发展。ATDC通过β-连环蛋白诱导的机制上调小鼠和人PanIN病变中的CD 44，导致诱导以Zeb 1和Snail 1表达为特征的上皮向间质转化（EMT）表型。ATDC的敲低阻断小鼠和人PDA细胞中的侵袭，并且该作用通过β-连环蛋白和CD 44介导。在这个提议中，我们假设ATDC是EMT的近端调节因子，并驱动胰腺癌的进展和转移，从而作为一个重要的治疗靶点。为了剖析ATDC在胰腺癌中的作用，我们将：1）使用新型基因工程小鼠模型研究ATDC在胰腺肿瘤发生中的作用; 2）表征ATDC诱导PDA中侵袭性表型的分子机制;和3）确定胰腺癌中ATDC上调的机制。

 DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma (PDA) is a deadly disease characterized by late diagnosis, aggressive invasion of surrounding tissues, and early metastasis. Patients with stage 1A disease have a 30% 5 year survival rate following resection, highlighting that PDA metastasizes early in patients, however, the molecular mechanisms driving early metastasis in PDA are not understood. We have recently found that the majority of human pancreatic adenocarcinomas have elevated expression of the Ataxia-Telangiectasia Group D Associated (ATDC) gene and that ATDC has an oncogenic function in pancreatic cancer through Wnt pathway activation and -catenin stabilization. Using newly created genetically engineered mouse models of pancreatic cancer, we have now identified a previously unknown role for ATDC in pancreatic cancer, where ATDC is upregulated during the early PanIN stage of tumorigenesis, and in the presence of oncogenic Kras, accelerates PanIN progression and the development of invasive and metastatic tumors. ATDC upregulates CD44 in mouse and human PanIN lesions through a -catenin-induced mechanism, resulting in the induction of an epithelial to mesenchymal transition (EMT) phenotype characterized by expression of Zeb1 and Snail1. Knockdown of ATDC blocks invasion in mouse and human PDA cells and this effect is mediated through -catenin and CD44. In this proposal, we hypothesize that ATDC is a proximal regulator of EMT and drives progression and metastasis of pancreatic cancer, thus serving as an important therapeutic target. To dissect the role of ATDC in pancreatic cancer, we will: 1) investigate the role of ATDC in pancreatic tumorigenesis using novel genetically engineered mouse models; 2) characterize the molecular mechanisms by which ATDC induces an invasive phenotype in PDA; and 3) determine the mechanism of ATDC upregulation in pancreatic cancer.