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期生存：转移和/或对放/化疗的抵抗。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，而其基础是揭示潜在的分子机制。两种细胞程序/途径--上皮-间充质转化(EMT)和河马途径--被证明发挥了关键作用。在拟议的项目中，我们的目标是确定这两个致癌程序/途径之间的直接功能相互作用，这两个致癌程序/途径在癌细胞中发挥类似的作用。我们已经证明，中心EMT激活剂ZEB1类似于致癌HIPPO途径的主要下游效应因子YAP，通过在癌细胞中诱导转移级联和施加干性和耐药表型而成为主要的致癌因素。我们的初步数据表明，ZEB1直接与YAP相互作用，从而连接了两条致癌途径。我们现在想要确定直接和功能相互作用的特征，确定其潜在的分子机制和后果，并验证其翻译和临床潜力。这一结果将成为干预恶性肿瘤进展和治疗抵抗的新的治疗干预策略的基础。

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.