Project Details
Projekt
Zeb1-mediated mechanisms of the EMT-associated ferroptosis sensitivity
Applicants
Professor Dr. Thomas Brabletz; Dr. Simone Brabletz
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461704629
Zeb1-mediated mechanisms of the EMT-associated ferroptosis sensitivity Ferroptosis is a highly conserved cell death pathway, depending on an iron and oxygen-radical mediated peroxidation of phospholipids. Importantly, such phospholipids need to be composed of certain species of polyunsaturated fatty acids (PUFAs). In contrast to apoptosis, the prominent death pathway in differentiated cells (e.g. epithelial cells), ferroptosis can be executed predominantly in undifferentiated cells and cells with a (partial) mesenchymal phenotype. In cancer cells, this phenotype is often acquired by activation of the epithelial-mesenchymal transition (EMT) program, and associated with high metastatic competence and therapy-resistance. In the first funding period, we could demonstrate that the EMT-activating transcription factor Zeb1 strongly increases PUFA-levels via activation of the rate-limiting enzymes fatty acid desaturase 2 (FADS2) and elongation of very long chain fatty acid 5 (ELOVL5), whereas it decreases the counteracting monounsaturated fatty acids (MUFAs) by direct repression of stearyl Co-A desaturase 1 (SCD) and fatty acid synthase (FASN), which are critical for MUFA synthesis. Pharmacological inhibition of SCD further sensitised cancer cells with a (partial) mesenchymal phenotype to ferroptosis in a Zeb1 dependent manner, pointing to additional Zeb1 functions for increasing ferroptosis sensitivity. In this regard, we found that Zeb1 is involved in the uptake of iron that is instrumental in lipid peroxidation. Zeb1 led to a decrease of the classical iron importer Transferrin receptor 1 (TfR1), but induces the expression of the short splice variant of a novel mesenchymal cell specific iron import receptor, CD44. In the second funding period, we plan to proof the importance of this specific splice variant, CD44s, for iron uptake and ferroptosis sensitivity and use our knowledge to establish possible therapy combinations targeting iron uptake and MUFA synthesis to induce ferroptosis activation as therapeutic strategy against highly aggressive cancer types.
DFG Programme
Priority Programmes
