Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer

最近出现了一种新的程序性细胞死亡机制，它与含有多不饱和脂肪酸（PUFA）的膜脂中氢过氧化物的积累有关。这种脂质过氧化物的积累导致脂质双分子层的不稳定，导致膜通透性增强，最终导致细胞死亡。为了对抗脂质损伤，细胞进化出了几种机制，通过将脂质过氧化物转化为醇来消除它们。其中一种机制涉及谷胱甘肽过氧化物酶4 (GPX4)，它使用还原性谷胱甘肽（GSH）作为辅助因子。另一种机制需要铁凋亡抑制蛋白1 (FSP1)，这是一种氧化还原酶，定位于质膜，在质膜上循环泛醇以维持其抗氧化功能。此外，已有研究表明，单不饱和脂肪酸（MUFA）还可以防止过量的脂质过氧化，从而降低细胞对铁下垂的敏感性。铁下沉在癌症中起着重要作用，因为肿瘤抑制功能丧失的癌基因激活驱动氧化应激，导致脂质过氧化增强。同时，含pufa的脂质也需要氧化代谢来驱动脂质介质的产生，从而促进癌症中的迁移、血管生成和免疫逃逸。因此，重要的是癌细胞维持过程的活性，以抵消过量的脂质过氧化和防止铁下垂。因此，靶向这些过程可能是治疗癌症的有希望的策略。在本项目中，我们将研究负责合成不同MUFA和PUFA物种的脂肪酸去饱和酶在确定癌细胞铁下垂易感性中的作用。我们将研究调节这些去饱和酶的表达对细胞脂质组成和铁下垂敏感性的影响。为了提供必需代谢物的生理水平，将在特殊配制的培养基中进行实验，这种培养基类似于来自不同器官的血浆和间质液的代谢物组成，以创造体内样的代谢生态位。我们还将使用肝癌小鼠模型来表征肿瘤发生过程中脂质代谢和抗铁致下沉机制的变化。最后，我们将在临床前模型中研究脂肪酸去饱和途径或GSH/GPX4轴的扰动是否会阻止肿瘤生长，以评估诱导铁下垂是否可能是一种治疗策略。

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.