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

EMT 激活剂 ZEB1 与 Yap/Taz/Hippo 通路在癌症中的相互作用

• 批准号: 314375996
• 负责人: Professor Dr. Thomas Brabletz
• 金额: --
• 依托单位: Lehrstuhl für Experimentelle Medizin I - Molekulare Pathogeneseforschung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/314375996?language=en
• 关键词: Interaction; EMT; activator; ZEB1; Yap

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.

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/或对放疗/化疗的耐药性。改善患者状况的唯一选择是开发对抗此类致命过程的新治疗策略，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）和海马通路——被证明起着至关重要的作用。在拟议的项目中，我们的目标是确定这两种致癌程序/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。我们已经证明，中枢emt激活因子ZEB1，类似于YAP，是致癌性hippo通路的主要下游效应因子，通过诱导转移级联并在癌细胞中施加干细胞和耐药性表型，是一个主要的致癌性因子。我们的初步数据表明，ZEB1直接与YAP相互作用，从而将两种致癌途径连接起来。我们现在想表征直接和功能的相互作用，确定其潜在的分子机制和后果，并验证其转化和临床潜力。该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抵抗。