Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis

• Published in: Science advances Vol. 10; no. 42; p. eadp6164
• Main Authors: More, Sanket, Bonnereau, Julie, Wouters, David, Spotbeen, Xander, Karras, Panagiotis, Rizzollo, Francesca, Killian, Theo, Venken, Tom, Naulaerts, Stefan, Vervoort, Ellen, Ganne, Maarten, Nittner, David, Verhoeven, Jelle, Bechter, Oliver, Bosisio, Francesca, Lambrechts, Diether, Sifrim, Alejandro, Stockwell, Brent R, Swinnen, Johannes V, Marine, Jean Christophe, Agostinis, Patrizia
• Format: Journal Article
• Language: English
• Published: United States 18.10.2024
• Subjects: Animals; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Cell Line, Tumor; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic; Humans; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mice; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adp6164

A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E ( ) as the top lipid-metabolism gene segregating the melanoma MITF /AXL proliferative/ferroptosis-resistant from MITF /AXL invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITF /AXL cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that expression in patients with melanoma is associated with resistance to ferroptosis, regardless of germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and expression as a potential biomarker for poor ferroptosis response in melanoma.