2. Academic Validation
  3. FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer

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

  • EMBO Mol Med. 2024 Jul;16(7):1533-1559. doi: 10.1038/s44321-024-00090-6.
Nicla Lorito # 1,  Angela Subbiani # 1,  Alfredo Smiriglia 1,  Marina Bacci 1,  Francesca Bonechi 1,  Laura Tronci 2,  Elisabetta Romano 1,  Alessia Corrado 3,  Dario Livio Longo 3,  Marta Iozzo 1,  Luigi Ippolito 1,  Giuseppina Comito 1,  Elisa Giannoni 1,  Icro Meattini 1 4,  Alexandra Avgustinova 5 6,  Paola Chiarugi 1,  Angela Bachi 2,  Andrea Morandi 7
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy.
  • 2 IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.
  • 3 Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Nizza 52, 10126, Torino, Italy.
  • 4 Radiation Oncology Unit, Oncology Department, Azienda Ospedaliero Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
  • 5 Institut de Recerca Sant Joan de Déu, Carrer Santa Rosa 39-57, 08950, Esplugues de Llobregat, Spain.
  • 6 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.
  • 7 Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134, Florence, Italy. andrea.morandi@unifi.it.
  • # Contributed equally.
PMID: 38926633 DOI: 10.1038/s44321-024-00090-6
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.

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