Criscuolo, Daniela (2022) Role of metabolic reprogramming in the development of ovarian cancer platinum resistance. [Tesi di dottorato]

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Ovarian cancer (OC) is the most aggressive gynecological malignancy. High grade serous ovarian cancer (HGSOC) is the most common and lethal type of ovarian cancer. Although HGSOC patients are initially extremely sensitive to standard first-line platinum-based chemotherapy, the majority relapse and progressively become chemoresistant. Resistance to platinum compounds results from multiple genetic and epigenetic mechanisms. In the last decade, it has become clear that metabolic changes affect drug response in several cancers, identifying metabolic reprogramming as an important mechanism of drug resistance. We have previously demonstrated, in patient-derived HGSOC cells, that platinum-resistance is driven by metabolic shift toward oxidative phosphorylation via activation of an inflammatory response. Interestingly, we identified low expression of the molecular chaperone TRAP1 as key determinant of the metabolic rewiring associated with cisplatin resistance, due to its involvement in the regulation of mitochondrial respiration. Starting from these observations, we aimed at further investigating the role of metabolic remodelling in the development of acquired resistance in HGSOC cells. To this purpose, we performed a multi-omics approach, including metabolomics and gene expression analysis, in order to identify the metabolic alterations present in drug-resistant cells. Cholesterol homeostasis and antioxidant defences emerged as dysregulated processes in chemoresistant cells. In this work, we demonstrate that platinum-resistant HGSOC cells exhibit a remodelling of cholesterol metabolism, with reduced cholesterol biosynthesis and increased uptake of exogenous cholesterol. Accordingly, enzymes involved in cholesterol synthesis such as FDPS and OSC are downregulated, whereas expression of LDL receptor, responsible for extracellular cholesterol uptake, is upregulated. Moreover, we show that reduced cholesterol biosynthesis is functional to the acquisition of drug resistance. Indeed, inhibition of cholesterol synthesis by lovastin reduces cisplatin-induced apoptosis in chemosensitive cells, while lipid stripping from culture media restores cisplatin sensitivity in chemoresistant cells, at least partially through a re-activation of cholesterol biosynthetic pathway. In patients, FDPS and LDLR show opposite correlation with overall survival, being the first directly associated to better survival and the latter associated to worse survival. In addition, we show that drug resistant cells exhibit unexpected alterations of the antioxidant network. Indeed, several studies have associated drug resistance with increased GSH levels, due to its role as cisplatin buffering system; conversely, GSH has also been reported to contribute to cisplatin-mediated cytotoxicity, as it is believed to be the main cytoplasmic target of cisplatin. We observed reduced intracellular GSH levels and compensatory increased expression of thioredoxin reductase in cisplatin-resistant cells. Accordingly, cisplatin-resistant cells show reduced levels of enzymes involved in GSH synthesis and increased sensitivity to oxidative stress inducers. Also, cisplatin treatment triggers accumulation of reduced GSH in both sensitive and resistant cells. Overall, our data highlight the important role played by rewired cholesterol metabolism in modulating cisplatin sensitivity and suggest that cisplatin treatment could positively select cancer cells which are independent of GSH for the maintenance of redox balance, and thus less sensitive to cisplatin-induced oxidative stress.

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