De rol van lysosomaal ijzertransport in de ferroptosegevoeligheid van geneesmiddelresistente melanoomcellen

Ferroptosis is a recently discovered form of iron-dependent, genetically regulated, necrotic cell death driven by loss-of function of the lipid repair enzyme glutathione peroxidase 4 (GPX4), which results in accumulation of lipid hydroperoxides and cell death. Moreover, a new ferroptosis suppression pathway, governed by the ferroptosis suppressor protein 1 (FSP1), has been recently defined. Accumulating evidence suggests that this type of regulated necrotic cell death represents a cancer cell vulnerability caused by the incorporation of polyunsaturated fatty acids (PUFAs) into cellular membranes, thus rendering cancer cells more susceptible to lipid peroxidation and ferroptosis. In the case of melanoma, ferroptosis-inducing agents combined with the BRAF kinase inhibitor vemurafenib, have been shown to reduce colony formation of undifferentiated melanoma cells in vitro, possibly because of their lower levels of glutathione (GSH). However, both the in vivo effects of ferroptosis-inducing agents and the mechanistic underpinning of ferroptosis susceptibility or resistance mechanisms in melanoma cells have remained largely undefined. Likewise, it remains largely unexplored whether ferroptosis-dying cancer cells are immunosuppressive or favor the establishment of anti-tumor immunity, in spite of emerging data indicating that Interferon gamma liberated by cytotoxic CD8+ T cells after immune checkpoint-based immunotherapy kills cancer cells through lipid-peroxidation mediated ferroptosis. In this study, using a multidisciplinary approach, including single cells analysis and in vivo studies, we aim to unravel the signaling network modulating the ferroptosis vulnerability of melanoma cells, and the immunological consequences of this type of cell death.