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The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer

Nature Cell Biology volume 19, pages 518529 (2017) | Download Citation

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Abstract

Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-to-mesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting metastasis has recently been challenged, in particular concerning effects of the Snail and Twist EMT transcription factors (EMT-TFs) in pancreatic cancer. In contrast, we show here that in the same pancreatic cancer model, driven by Pdx1-cre-mediated activation of mutant Kras and p53 (KPC model), the EMT-TF Zeb1 is a key factor for the formation of precursor lesions, invasion and notably metastasis. Depletion of Zeb1 suppresses stemness, colonization capacity and in particular phenotypic/metabolic plasticity of tumour cells, probably causing the observed in vivo effects. Accordingly, we conclude that different EMT-TFs have complementary subfunctions in driving pancreatic tumour metastasis. Therapeutic strategies should consider these potential specificities of EMT-TFs to target these factors simultaneously.

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Acknowledgements

We thank B. Schlund, E. Bauer and J. Pfannstiel, as well as U. Appelt and M. Mroz (Core Unit Cell Sorting and Immunomonitoring, FAU Erlangen, Germany) for technical assistance and R. Eccles for critical reading of the manuscript. We are grateful to D. Saur (Department of Internal Medicine, TU Munich, Germany) for providing the KPCS cell lines. We thank J. C. Wu, from Stanford University, for the MSCV-LUC_EF1-GFP-T2A-Puro plasmid. This work was supported by grants to T.B., S.B., M.B. and M.P.S. from the German Research Foundation (SFB850/A4, B2, Z1 and DFG BR 1399/9-1, DFG 1399/10-1, DFG BR4145/1-1) and from the German Consortium for Translational Cancer Research (DKTK).

Author information

Author notes

    • Marc P. Stemmler
    •  & Thomas Brabletz

    These authors jointly supervised this work.

Affiliations

  1. Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany

    • Angela M. Krebs
    • , María Lasierra Losada
    • , Simone Brabletz
    • , Marc P. Stemmler
    •  & Thomas Brabletz
  2. University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, 79104 Freiburg, Germany

    • Angela M. Krebs
  3. German Cancer Consortium (DKTK), 79106 Freiburg, Germany

    • Angela M. Krebs
    • , Melanie Boerries
    • , Hauke Busch
    • , Wilfried Reichardt
    •  & Peter Bronsert
  4. German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany

    • Angela M. Krebs
    • , Melanie Boerries
    • , Hauke Busch
    • , Wilfried Reichardt
    •  & Peter Bronsert
  5. Department of General and Visceral Surgery, University of Freiburg Medical Center, Hugstetter Strasse 55, 79106 Freiburg, Germany

    • Julia Mitschke
    •  & Otto Schmalhofer
  6. Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research (IMMZ), Albert-Ludwigs-University Freiburg, Stefan-Meier-Strasse 17, 79106 Freiburg, Germany

    • Melanie Boerries
    •  & Hauke Busch
  7. Department of Internal Medicine 5, Hematology and Oncology, Universitätsklinikum, FAU University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany

    • Martin Boettcher
    •  & Dimitrios Mougiakakos
  8. Department of Radiology Medical Physics, University Medical Center, Freiburg, Breisacher Strasse 60a, 79106 Freiburg, Germany

    • Wilfried Reichardt
  9. Institute of Pathology and Comprehensive Cancer Center, University Medical Center, Freiburg, Breisacher Strasse 115a, 79106 Freiburg, Germany

    • Peter Bronsert
  10. Edinburgh Cancer Research Centre, Institute of Genetics & Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK

    • Valerie G. Brunton
  11. Department of Surgery, Universitätsklinikum, FAU University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany

    • Christian Pilarsky
  12. Chair of Genetics, Nikolaus-Fiebiger-Center for Molecular Medicine, Department Biology, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany

    • Thomas H. Winkler

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Contributions

A.M.K. planned and carried out experiments and wrote the manuscript. J.M. carried out mouse experiments. M.L.L. carried out drug studies. O.S. generated the floxed Zeb1 allele. M.B. and H.B. carried out bioinformatics analyses. M.B. and D.M. carried out metabolic tests. W.R. carried out MRI analyses. P.B. carried out histological analyses. V.G.B. established mouse models. C.P. generated cell lines. T.H.W. carried out mouse experiments. S.B. generated the floxed Zeb1 allele, and planned and carried out experiments. M.P.S. generated the floxed Zeb1 allele, planned and carried out mouse experiments, was involved in coordination and wrote the manuscript. T.B. planned and coordinated the project, analysed data and wrote the manuscript. M.P.S. and T.B. contributed equally and share senior authorship.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marc P. Stemmler or Thomas Brabletz.

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https://doi.org/10.1038/ncb3513

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