Project 3
Regulation of ferroptosis at the intersection of lipid metabolism and cell death
Ferroptosis, a form of regulated cell death triggered by accumulation of toxic lipid hydroperoxides, is under intensive investigation in various diseases. Although several cancer lineages show high ferroptosis sensitivity, cancer cells have developed strategies to avoid ferroptotic cell death by promoting global lipid remodeling or by increasing the production of anti-oxidants, including reduced glutathione (GSH) and ubiquinol (CoQ10H2). We previously found that clear cell renal cell carcinoma (ccRCC) cells are highly dependent on GSH synthesis to prevent ferroptosis caused by excess accumulation of lipids (Miess et al., Oncogene 2018). Furthermore, the group contributed to a study identifying the ferroptosis suppressor protein 1 (FSP1) as a glutathione independent inhibitor of ferroptosis (Doll et al., Nature 2019). Several ongoing projects in the division are currently investigating mechanisms of ferroptosis sensitivity in cancer.
As part of a DFG-funded consortium, we investigated the metabolic reprogramming which takes place during oncogene-induced senescence. Transcriptomics, metabolomics and lipidomics analysis exposed distinct changes in lipid metabolism in BRafV600E-senescent human fibroblasts. Senescent cells showed an increased arachidonic acid metabolism, resulting in the secretion of oxylipins, a phenotype previously associated with senescence [20]. In addition, BRAFV600E-senescent cells accumulated triglycerides (TAG) and were less sensitive towards ferroptosis. Inhibition of the rate-limiting TAG synthesis enzyme diacylglycerol O-acyltransferase (DGAT) restored sensitivity towards ferroptosis in senescent cells through the redirection of specific PUFAs to membrane lipids. These results demonstrate that remodeling of the cellular lipidome contributes to ferroptosis resistance of senescent cells.
We are also investigating the role of the metabolism of essential fatty acids, particularly the omega-6 fatty acid linoleic acid, in determining ferroptosis sensitivity of renal cancer cells. Using lipidomic analysis of cancer cells treated with exogenous linoleic acid, our study revealed the importance of fatty acid desaturase 2 (FADS2) in controlling the production of highly unsaturated fatty acids for the synthesis of plasmalogen lipids that are particularly sensitive to peroxidation to induce ferroptosis. Furthermore, we are investigating how different metabolic microenvironments determine ferroptosis sensitivity of cancer cells during metastasis formation.