Lorito 2024 EMBO Mol Med
| Lorito N, Subbiani A, Smiriglia A, Bacci M, Bonechi F, Tronci L, Romano E, Corrado A, Longo DL, Iozzo M, Ippolito L, Comito G, Giannoni E, Meattini I, Avgustinova A, Chiarugi P, Bachi A, Morandi A (2024) FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer. EMBO Mol Med [Epub ahead of print]. https://doi.org/10.1038/s44321-024-00090-6 |
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 (2024) EMBO Mol Med
Abstract: 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. • Keywords: Desaturases, Ferroptosis, Lipid Droplets, Lipid Metabolism, Polyunsaturated Fatty Acids • Bioblast editor: Plangger M • O2k-Network Lab: IT Florence Morandi A
Labels: MiParea: Respiration
Pathology: Cancer
Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell Preparation: Intact cells
Coupling state: ET, LEAK, ROUTINE
Pathway: ROX
HRR: Oxygraph-2k
2024-07
