Decoding the role of cysteine metabolism in angiogenesis

Angiogenesis is the process by which new blood vessels are formed from pre existing ones in response to signals triggered by pathophysiological conditions, such as wound healing or cancer. In this study, we aim to decode the role of cysteine in angiogenesis, specifically how its deprivation, or the inhibition of the transsulfuration pathway involved in cysteine synthesis affect endothelial cell survival by triggering ferroptosis. Since endothelial cells can exist in different metabolic states (quiescent, QECs, or proliferating, PECs), we investigate whether cysteine deprivation has differential effects depending on the cell's metabolic state. Our data show that cysteine deprivation leads to cell death by ferroptosis in PECs, a form of cell death characterized by the accumulation of lipid peroxides, culminating in membrane rupture. In contrast, QECs exhibit an inherent resistance to cysteine starvation compared to PECs, likely because, unlike PECs that rely on xCT (the cystine/glutamate antiporter) as their main source of cysteine, QECs use TSP as their primary cysteine source. Extracellular cysteine limitation is a feature of various tumors. A deeper understanding of the pathways involved in resistance to cysteine starvation could aid in developing new therapies aimed at inhibiting these pathways, ultimately improving prognosis by targeting the formation of new blood vessels, essential for tumor growth.