ATDC Function in Human Pancreatic Adenocarcinoma

 描述(申请人提供)：胰腺癌(PDA)是一种致命的疾病，其特点是诊断晚，侵袭周围组织，早期转移。1A期患者术后5年存活率为30%，说明动脉导管未闭患者早期发生转移，但其早期转移的分子机制尚不清楚。我们最近发现，大多数人胰腺癌都有共济失调-毛细血管扩张D组相关基因(ATDC)的高表达，ATDC通过激活Wnt通路和稳定-连接素而在胰腺癌中发挥致癌作用。利用新建立的胰腺癌基因工程小鼠模型，我们现在已经确定了ATDC在胰腺癌中的一个以前未知的角色，其中ATDC在肿瘤发生的早期上调，在致癌Kras的存在下，加速Panin进展和侵袭和转移肿瘤的发展。ATDC通过-连环蛋白诱导机制上调小鼠和人类Panin病变中的CD44值，导致以ZEB1和Snail1表达为特征的上皮向间充质转化表型的诱导。ATDC基因敲除可阻断小鼠和人动脉导管上皮细胞的侵袭，这种作用是通过-连环蛋白和CD44介导的。在这个方案中，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，从而成为一个重要的治疗靶点。为了分析ATDC在胰腺癌中的作用，我们将：1)利用新的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侵袭性表型的分子机制；3)确定ATDC在胰腺癌中上调的机制。

 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.