Cancer promoting transcriptional enhancers controlled by the EMT-activator ZEB1

• Applicants: Professor Dr. Thomas Brabletz; Dr. Simone Brabletz
• Subject Area: Pathology ; Hematology, Oncology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416775465

To date, the vast majority of cancer related deaths is caused by the formation of distant metastases. Thus, it is of utmost importance to better understand and predict the metastatic process. During the last two decades we and others could identify cancer cell plasticity, mediated by the embryonic program of Epithelial to Mesenchymal Transition (EMT) and its reverse process (MET), to be a crucial trait driving the metastatic cascade. Our work focuses on the transcription factor ZEB1, a major EMT inducer and known repressor of epithelial genes. We have shown that in aggressive cancers, ZEB1 can turn into a transcriptional activator of tumor-promoting genes. Lately, gene activation via distant transcriptional enhancers emerged as an important metastasis promoting mechanism. Active enhancers are even considered as prognostic and potentially diagnostic tumor markers. Since we have evidence that ZEB1 functions in enhancer activation, we now plan to characterize ZEB1 dependent enhancer regions on a genome wide level. Further, we want to annotate those enhancers to the respective regulated genes and characterize their functions in tumor cell biology. We expect to achieve knowledge about a novel aspect of ZEB1 dependent pro-metastatic functions and to identify novel tumor promoting enhancers that might serve as potential prognostic and diagnostic tools.

• DFG Programme: Research Grants