Interaction of the EMT-activator ZEB1 and the Yap/Taz/Hippo-pathway in cancer

许多实体癌可以通过手术切除成功切除。然而，两个主要的临床问题阻碍了癌症患者的治愈或长时间存活：转移和/或对放射/化学疗法的抗性。改善患者状况的唯一选择是开发新的治疗策略来对抗这种致命的过程，其基础是揭示潜在的分子机制。两个细胞程序/途径-上皮-间充质转化（EMT）和海马途径-发挥了至关重要的作用。在拟议的项目中，我们的目标是确定这两个致癌程序/途径的直接功能相互作用，它们在癌细胞中发挥类似的作用。我们已经表明，中央EMT激活剂ZEB 1，类似于致癌Hippo通路的主要下游效应物雅普，是一种主要的致癌因子，通过诱导转移级联反应并在癌细胞中施加耐药性和耐药性表型。我们的初步数据表明，ZEB 1直接与雅普相互作用，从而连接两个致癌途径。我们现在想要表征直接和功能性相互作用，确定其潜在的分子机制和后果，以及验证其翻译和临床潜力。这些结果将为新的治疗干预策略提供基础，以干预恶性肿瘤的进展和治疗耐药性。

Many solid cancers can be successfully removed by surgical resection. However two main clinical problems impede a cure or a long time survival of cancer patients: Metastasis and/or resistance to radio-/chemotherapy. The only option to improve the patients situation is the development of novel therapeutic strategies fighting such fatal processes and the basis for that is to uncover the underlying molecular mechanisms. Two cellular programmes/pathways - the epithelial-mesenchymal transition (EMT) and the Hippo-pathway - turned out to play crucial roles. In the proposed project, we aim to determine a direct functional interaction of these two oncogenic programmes/pathways, which exert similar effects in cancer cells. We have shown that the central EMT-activator ZEB1, similar to YAP, the major downstream effector of the oncogenic Hippo-pathway, is a major oncogenic factor by inducing the metastatic cascade and imposing a stemness- and drug resistance phenotype in cancer cells. Our preliminary data indicate that ZEB1 directly interacts with YAP, thus linking both oncogenic pathways. We now want to characterize the direct and functional interaction, determine its underlying molecular mechanisms and consequences as well as to validate its translational and clinical potential. The results will be the basis for novel therapeutic intervention strategies to interfere with malignant tumor progression and therapy resistance.