2. Academic Validation
  3. Metabolic plasticity and optimal redox homeostasis are essential for efficient metastatic colonization

Metabolic plasticity and optimal redox homeostasis are essential for efficient metastatic colonization

  • Mol Metab. 2026 Jul:109:102382. doi: 10.1016/j.molmet.2026.102382.
Ece Grace 1,  Deyu Zou 2,  Romy Böttcher-Loschinski 3,  Martin Böttcher 4,  Harald Schuhwerk 5,  Yussuf Hajjaj 1,  Annemarie Schwab 1,  Simon Brandt 1,  Ana Clavel Ezquerra 1,  Witold Szymanski 6,  Johannes Graumann 6,  Philipp Arnold 7,  Renato Liguori 8,  Fulvia Ferrazzi 9,  Constantin P Krempe 10,  L M Nascentes Melo 11,  Gabriele Allies 11,  Sven W Meckelmann 12,  Dirk Mielenz 13,  Simone Brabletz 14,  Dimitrios Mougiakakos 15,  Alpaslan Tasdogan 11,  Thomas Brabletz 14,  Marc P Stemmler 16
Affiliations

Affiliations

  • 1 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 2 Department of Hematology, Oncology and Cell Therapy, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany.
  • 3 Department of Hematology, Oncology and Cell Therapy, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Magdeburg Centre for Cell and Immune Therapy (MAZI), Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
  • 4 Department of Hematology, Oncology and Cell Therapy, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Magdeburg Centre for Cell and Immune Therapy (MAZI), Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; Healthcampus Immunology, Inflammation and Infectiology (GC-I3), Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany.
  • 5 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany; Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
  • 6 Institute of Translational Proteomics & Core Facility Translational Proteomics, Philipps-Universität Marburg, Marburg, Germany.
  • 7 Institute of Functional and Clinical Anatomy, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 8 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany; Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 9 Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Bavarian Cancer Research Center (BZKF), Erlangen, Germany.
  • 10 Department of Dermatology, University Hospital Essen, German Cancer Consortium (DKTK) and Research Alliance Ruhr, Research Center One Health, Campus Essen, Essen, Germany; Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
  • 11 Department of Dermatology, University Hospital Essen, German Cancer Consortium (DKTK) and Research Alliance Ruhr, Research Center One Health, Campus Essen, Essen, Germany.
  • 12 Applied Analytical Chemistry, University of Duisburg-Essen, Essen, Germany.
  • 13 Department of Translational Immunology, Department of Internal Medicine 3, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany.
  • 14 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Bavarian Cancer Research Center (BZKF), Erlangen, Germany.
  • 15 Department of Hematology, Oncology and Cell Therapy, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany; Magdeburg Centre for Cell and Immune Therapy (MAZI), Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; Healthcampus Immunology, Inflammation and Infectiology (GC-I3), Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany; Center for Health and Medical Prevention - CHAMP, Otto-von-Guericke University, Magdeburg, Germany.
  • 16 Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany. Electronic address: [email protected].
PMID: 42155637 DOI: 10.1016/j.molmet.2026.102382
Abstract

Cancer cells dynamically reprogram their metabolism to adapt to changing microenvironmental conditions during tumor growth and metastatic dissemination. Metastasis of solid tumors-the principal cause of cancer-related mortality-is often driven through activation of epithelial-mesenchymal transition (EMT), regulated by the transcription factor ZEB1, which is frequently upregulated during tumor progression. To investigate the role of metabolic plasticity in metastasis, we employed murine pancreatic ductal adenocarcinoma (PDAC) cell lines with distinct EMT states, ZEB1 expression and lung colonization capacities. Highly plastic epithelial-type Cancer cells (KPCepi) efficiently colonize the lung, whereas Zeb1-deficient Cancer cells (KPCZ) with compromised metabolic plasticity show markedly reduced colonization, correlated with absent glycolytic reserve, mitochondrial dysfunction, and reduced anti-oxidant metabolite levels. Interestingly, mesenchymal-type Cancer cells (KPCmes) also exhibit poor lung colonization despite retaining normal glycolytic capacity and a high proportion of functional mitochondria; however, similar to KPCZ cells, they display diminished levels of detoxifying metabolites. Low metastatic capacity correlates with increased susceptibility to Ferroptosis even in epithelial-type KPCZ cells, indicating a limited ability to counteract Reactive Oxygen Species under stress. Together, these findings demonstrate that metabolic plasticity and redox homeostasis are essential prerequisites for efficient lung colonization. Thus, concurrent targeting of metabolic adaptability and redox buffering may represent a promising strategy to prevent metastasis in aggressive PDAC tumors.

Keywords

Cancer; Cellular plasticity; Epithelial-to-mesenchymal transition; Ferroptosis; Glycolysis; Metabolism; Metastasis; Mitochondria; Pancreatic ductal adenocarcinoma (PDAC); Redox balance.

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