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 recently emerged as a novel mechanism of programmed cell death that is mechanistically connected to the accumulation of hydroperoxides in membrane lipids that contain poly-unsaturated fatty acids (PUFA). Accumulation of such lipid peroxides causes destabilisation of the lipid bilayer, leading to enhanced membrane permeability and ultimately cell death. To counteract lipid damage, cells have evolved several mechanisms that eliminate lipid peroxides by turning them into alcohols. One of these mechanisms involves the glutathione peroxidase 4 (GPX4), which uses reduced glutathione (GSH) as a cofactor. Another mechanism requires the ferroptosis suppressor protein 1 (FSP1), a oxidoreductase that is localised to the plasma membrane where it recycles ubiquinol to maintain its anti-oxidant function. Moreover, it has bene shown that mono-unsaturated fatty acids (MUFA) also prevent excess lipid peroxidation, thereby reducing the sensitivity of cells towards ferroptosis. Ferroptosis plays an important role in cancer, as oncogene activation of loss of tumour suppressor function drives oxidative stress that leads to enhanced lipid peroxidation. At the same time, oxidative metabolism of PUFA-containing lipids is also required to drive the production of lipid mediators that promote migration, angiogenesis 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. In this project, we will investigate the role of fatty acid desaturases responsible for the synthesis of different MUFA and PUFA species in defining ferroptosis susceptibility in cancer cells. We will investigate the effect of modulating the expression of these desaturases on cellular lipid composition and ferroptosis sensitivity. In order to provide physiological levels of essential metabolites, experiments will be conducted in specially formulated media that resemble the metabolite composition of plasma and interstitial fluids from different organs to create in vivo-like metabolic niches. We will also use a mouse model of liver cancer to characterise changes in lipid metabolism and anti-ferroptotic mechanisms during tumourigenesis. Finally, we will investigate whether perturbation of fatty acid desaturation pathways or the GSH/GPX4 axis blocks tumour growth in a preclinical model to evaluate whether induction of ferroptosis could be a therapeutic strategy.
DFG Programme
Priority Programmes
