The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
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DOI：
10.1038/ncb3513
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发表时间：
2017-05-01
影响因子：
21.3
通讯作者：
Brabletz, Thomas
中科院分区：
文献类型：
--
作者：
Krebs, Angela M.;Mitschke, Julia;Brabletz, Thomas
转移是癌症相关死亡的主要原因。上皮-间质转化程序（部分EMT）的部分激活被认为是肿瘤从起始到转移进展的主要驱动因素。然而，EMT在促进转移中的作用最近受到了挑战，特别是关于Snail和Twist EMT转录因子（EMT-TF）在胰腺癌中的作用。相反，我们在这里表明，在相同的胰腺癌模型中，由Pdx 1-cre介导的突变Kras和p53激活（KPC模型）驱动，EMT-TF Zeb 1是形成前体病变，侵袭和转移的关键因素。Zeb 1的耗尽抑制了肿瘤细胞的干性、定殖能力，特别是表型/代谢可塑性，可能导致观察到的体内效应。因此，我们得出结论，不同的EMT-TF在驱动胰腺肿瘤转移中具有互补的子功能。治疗策略应考虑EMT-TF的这些潜在特异性，以同时靶向这些因素。
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.