FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer
Por:
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 and Morandi A
Publicada:
15 jul 2024
Ahead of Print:
1 jun 2024
Resumen:
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.
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.
Filiaciones:
Lorito N:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Subbiani A:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Smiriglia A:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Bacci M:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Bonechi F:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Tronci L:
IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy
Romano E:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Corrado A:
Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, 10126, Torino, Italy
Longo DL:
Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, 10126, Torino, Italy
Iozzo M:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Ippolito L:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Comito G:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Giannoni E:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Meattini I:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Radiation Oncology Unit, Oncology Department, Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy
Avgustinova A:
Institut de Recerca Sant Joan de Déu, Carrer Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain
Chiarugi P:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
Bachi A:
IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy
Morandi A:
Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy
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