FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer

• Published in: EMBO molecular medicine 2024-07, Vol.16 (7), p.1533-1559
• Main Authors: Lorito, Nicla, Subbiani, Angela, Smiriglia, Alfredo, Bacci, Marina, Bonechi, Francesca, Tronci, Laura, Romano, Elisabetta, Corrado, Alessia, Longo, Dario Livio, Iozzo, Marta, Ippolito, Luigi, Comito, Giuseppina, Giannoni, Elisa, Meattini, Icro, Avgustinova, Alexandra, Chiarugi, Paola, Bachi, Angela, Morandi, Andrea
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Cell Line, Tumor; Delta-5 Fatty Acid Desaturase; Desaturases; EMBO03; EMBO07; EMBO21; Fatty Acid Desaturases - genetics; Fatty Acid Desaturases - metabolism; Female; Ferroptosis; Ferroptosis - drug effects; Humans; Lipid Droplets; Lipid Metabolism; Mice; Molecular Medicine; Polyunsaturated Fatty Acids; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology
• ISSN: 1757-4684; 1757-4676; 1757-4684
• DOI: 10.1038/s44321-024-00090-6

Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients. Synopsis The availability of intracellular polyunsaturated fatty acids (PUFA) depends on fatty acid desaturases 1 and 2 (FADS1/2), expressed at higher levels in aggressive triple-negative breast cancers (TNBC) highly susceptible to ferroptosis. FADS1/2 are highly expressed in a subset of TNBC with a poorer prognosis. FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents. FADS1/2 ablation decreases PUFA/MUFA ratio and renders TNBC insensitive to pro-ferroptosis agents. Lipid droplets (LD) maintain PUFA/MUFA intracellular balance and when targeted enhance cell death triggered by ferroptosis induction. The availability of intracellular polyunsaturated fatty acids depends on FADS1/2 desaturases, expressed at higher levels in aggressive triple-negative breast cancers highly susceptible to ferroptosis.