Zeb1-mediated control of the PUFA/MUFA ratio in EMT-associated ferroptosis sensitivity

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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. We could demonstrate that the EMT-activating transcription factor Zeb1 strongly increases PUFA-levels, whereas it decreases the counteracting monounsaturated fatty acids (MUFAs). We will proof if Zeb1 directly regulates the expression of the rate-limiting enzymes for PUFA- vs. MUFA-synthesis, i.e. downregulates expression of stearyl Co-A desaturase 1 (SCD1), which is critical for MUFA synthesis, and upregulates expression of fatty acid desaturase 2 (FADS2) and elongation of very long chain fatty acid 5 (ELOVL5), both rate-limiting enzymes for PUFA synthesis. We will further proof if altered expression and function of these enzymes accounts for the Zeb1-associated ferroptosis sensitivity in cancer cells with a (partial) mesenchymal phenotype. Finally, we will test if specific modulators of their expression and function will support ferroptosis activation as therapeutic strategy against highly aggressive cancer types.