Role of the EMT activator ZEB1 in pancreatic cancer invasion, dissemination and metastasis

转移是癌症相关死亡的主要原因。我们认为，转移是由上皮-间充质转化(EMT)触发的，能够扩散和随后的上皮再分化(MET)，从而能够转移定植。这种肿瘤细胞可塑性的概念现在得到了实验验证，并进一步扩展到癌症干细胞的概念，表明EMT不仅赋予癌细胞运动能力，而且还维持干细胞的特性。我们发现EMT激活剂ZEB1在细胞培养或异种移植模型中触发了癌细胞的可塑性和肿瘤的进展。我们现在使用有条件的ZEB1基因敲除小鼠来研究ZEB1缺失对胰腺癌遗传小鼠模型的影响。我们的初步结果表明，ZEB1基因敲除肿瘤以及衍生的细胞系固定在分化的上皮状态，并显示出较少的转移。在拟议的项目中，我们计划详细揭示ZEB1是如何在这个小鼠模型中刺激转移和肿瘤细胞可塑性的。我们还想扩大我们对ZEB1在循环和扩散肿瘤细胞的形成和功能中的作用以及在耐药性发展中的作用的分析。了解这些分子联系将是开发新的治疗策略以预防和对抗转移的基础。

Metastasis is the main cause of cancer associated death. We proposed that metastasis is triggered by an epithelial-mesenchymal transition (EMT), enabling dissemination and a subsequent epithelial re-differentiation (MET), enabling metastatic colonization. This concept of tumor cell plasticity is now experimentally validated and further extended to the cancer stem cell concept, by showing that EMT not only confers cancer cell motility but also maintains stem cell properties. We showed that the EMT-activator ZEB1 triggers cancer cell plasticity and tumor progression in cell culture or xenograft models. We now use a conditional Zeb1 knockout mouse to investigate the effects of Zeb1-depletion in a genetic mouse model for pancreatic cancer. Our preliminary results show that Zeb1 knockout tumors as well as derived cell lines are fixed in a differentiated, epithelial state and exhibit reduced metastasis. In the proposed project, we plan to uncover in detail how Zeb1 is stimulating metastasis and tumor cell plasticity in this mouse model. We also want to expand our analyses on the role of Zeb1 in the formation and function of circulating and disseminating tumor cells as well in the development of drug resistance. Understanding these molecular links will be the basis for developing new therapeutic strategies to prevent and fight metastasis.