Project Details
Projekt
Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer
Applicant
Professorin Dr. Almut Schulze
Subject Area
Cell Biology
Term
since 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 461705295
Ferroptosis has emerged as a novel mechanism of programmed cell death that is mechanistically connected to the accumulation of lipid hydroperoxides, leading to enhanced membrane permeability and cell death. Ferroptosis depends on the presence of lipids in the cell membrane that carry several double bonds within their fatty acid tails. Fatty acids with several double bonds are synthesised from essential fatty acids (omega-6 and omega-3) that are taken up by the cells and further modified through a process called essential fatty acid metabolism. The same process is also involved in the production of bioactive lipids that promote inflammation and immune evasion in cancer. It is therefore important that cancer cells maintain the activity of processes that counteract excess lipid peroxidation and prevent ferroptosis. Consequently, targeting these processes could be promising strategies for cancer treatment. Oncogene activation or loss of tumour suppressor function enhances oxidative stress in cancer cells making them highly dependent on anti-oxidant systems to prevent ferroptosis. One of these mechanisms involves the glutathione peroxidase 4 (GPX4) which converts lipid peroxides into non-toxic alcohols. We found that liver tissue contains low amounts of extracellular cystine, a nutrient requited for the production of glutathione to support the activity of GPX4, an important inhibitor of ferroptosis. Cancer cells forming metastasis in the liver therefore have to find alternative sources of cystine to prevent ferroptosis. In this project, we will investigate the role of essential fatty acid metabolism in modulating ferroptosis susceptibility in cancer. We will investigate the effect of modulating the expression and activity of enzymes involved in the metabolism of essential fatty acids on cellular lipid composition and ferroptosis sensitivity. Moreover, we will investigate whether cancer cells can degrade extracellular glutathione in order to access essential amino acids for anti-oxidant synthesis. We will also use mouse models to monitor the importance of essential fatty acid metabolism and enzymes involved in cysteine scavenging for tumour growth and metastasis formation. Finally, we will also investigate links between ferroptosis protection and immune evasion in cancer.
DFG Programme
Priority Programmes
