2. Academic Validation
  3. Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition

Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition

  • Nat Cell Biol. 2024 Jul 15. doi: 10.1038/s41556-024-01464-1.
Annemarie Schwab # 1,  Zhigang Rao # 2,  Jie Zhang 2,  André Gollowitzer 2,  Katharina Siebenkäs 1,  Nino Bindel 1,  Elisabetta D'Avanzo 1,  Ruthger van Roey 1,  Yussuf Hajjaj 1,  Ece Özel 1,  Isabell Armstark 1,  Leonhard Bereuter 2,  Fengting Su 2,  Julia Grander 2,  Ehsan Bonyadi Rad 2,  Arwin Groenewoud 3,  Felix B Engel 3 4,  George W Bell 5,  Whitney S Henry 5 6,  José Pedro Friedmann Angeli 7,  Marc P Stemmler 1,  Simone Brabletz # 1 4,  Andreas Koeberle # 8,  Thomas Brabletz # 9 10
Affiliations

Affiliations

  • 1 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 2 Michael Popp Institute and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innsbruck, Austria.
  • 3 Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 4 Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Bavarian Cancer Research Center (BZKF), Erlangen, Germany.
  • 5 Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • 6 Dept. of Biology, MIT, Cambridge, MA, USA.
  • 7 Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.
  • 8 Michael Popp Institute and Center for Molecular Biosciences (CMBI), University of Innsbruck, Innsbruck, Austria. andreas.koeberle@uibk.ac.at.
  • 9 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany. thomas.brabletz@fau.de.
  • 10 Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Bavarian Cancer Research Center (BZKF), Erlangen, Germany. thomas.brabletz@fau.de.
  • # Contributed equally.
PMID: 39009641 DOI: 10.1038/s41556-024-01464-1
Abstract

Therapy resistance and metastasis, the most fatal steps in Cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to Ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of Phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase Ferroptosis susceptibility in Cancer cells, which depends on the EMT transcription factor Zeb1. We demonstrate that Zeb1 increases the ratio of Phospholipids containing pro-ferroptotic polyunsaturated fatty acids over cyto-protective monounsaturated fatty acids by modulating the differential expression of the underlying crucial Enzymes stearoyl-Co-A desaturase 1 (SCD), fatty acid synthase (FASN), fatty acid desaturase 2 (FADS2), elongation of very long-chain fatty acid 5 (ELOVL5) and long-chain acyl-CoA synthetase 4 (ACSL4). Pharmacological inhibition of selected lipogenic Enzymes (SCD and FADS2) allows the manipulation of Ferroptosis sensitivity preferentially in high-Zeb1-expressing Cancer cells. Our data are of potential translational relevance and suggest a combination of Ferroptosis activators and SCD inhibitors for the treatment of aggressive cancers expressing high Zeb1.

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