Project Details
Projekt
EMT-dependent gene regulatory networks important for metastatic colonisation
Subject Area
Pathology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 569581119
To date, the most fatal step in cancer progression is metastasis. 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 that enables not only tumour cell-migration and -invasion, but also -survival, therapy resistance and immune evasion. We have recently shown that Zeb1, which is primarily known as repressor of epithelial genes, can also act as a transcriptional activator of tumour-promoting genes mainly via non-coding distal enhancer regions. This joint project started with the detailed analysis of Zeb1-dependent enhancers through the comprehensive bulk and single-cell chromatin characterisation of cell lines from a genetic mouse model of pancreatic cancer. The first candidate enhancer we have successfully identified using this strategy controls Nt5e, a gene encoding an immune dampening and metastasis promoting factor that lately emerged as a potential therapeutic target. Further, our genomic analyses revealed an unexpected layer of Zeb1-dependent gene regulation putatively involving mRNA dependent repression of microRNAs. In this proposal, we will systematically investigate this new mode of gene regulation where Zeb1 mRNA acts as a “sponge” / competitor for microRNAs involved in EMT and delineate how this impacts tumour cell plasticity and cancer progression. Using single-cell multiome methods that we have established in the previous funding period, we will study Zeb1-dependent regulatory networks, integrating all layers of transcriptional control as well as the dynamic adaptation, in a timecourse of in vivo lung colonisation. Using this data, we will be able to identify relevant upstream acting transcription factors as well as their downstream target genes or enhancers and microRNAs. To ensure translational relevance, we will further validate the most important regulatory hubs and their targets in the human disease context and perform functional testing regarding tumour progression and metastasis using advanced in vitro models including primary tissue cultures as well as in vivo mouse lung colonisation studies. We expect to achieve comprehensive knowledge about the various ZEB1/EMT dependent pro-metastatic functions that will enable the development of targeted prognostic and diagnostic tools as well as therapeutic strategies.
DFG Programme
Research Grants
