Therapeutic harnessing of iron-dependent cell death in melanoma; the ApolipoproteinE and ferroptosis link

During malignant progression, melanoma cells with mesenchymal-like properties invariably become resistant to a wide range of mainstay antimelanoma therapies. Hence understanding the resistance mechanisms, making melanoma cells escaping therapy-induced eradication, and finding new melanoma vulnerabilities, enabling specific killing of these drug-resistant cancer cells, are crucial challenges in biomedical research.  Emerging studies suggest that dedifferentiation towards a mesenchymal-like state in melanoma is coupled to an increased vulnerability to ferroptosis, a form of iron-dependent necrotic cell death driven by the accumulation of lipid peroxides in response to inhibition of glutathione peroxidase 4 (GPX4). While, these studies suggest a link between the lipid peroxidase pathway and a therapeutically exploitable vulnerability of drug-refractory melanoma cells, the mechanisms determining ferroptosis susceptibility in melanoma remain poorly defined. Our preliminary results suggest that changes in the melanoma’s polyunsaturated lipid profile and expression of the lipid binding protein Apolipoprotein E (APOE) act in concert to modulate ferroptosis-susceptibility of drug-resistant melanoma cells. Here we aim to unravel the molecular and in vivo mechanisms through which melanoma-associated APOE confers resistance to ferroptosis and track at the single cell levels via high-end mass cytometry the signaling network underlying the ferroptosis resistance in melanoma.