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Nat Cell Biol. 2017 May;19(5):518-529. doi: 10.1038/ncb3513. Epub 2017 Apr 17.

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

Author information

1
Department of Experimental Medicine 1, Nikolaus-Fiebiger-Center for Molecular Medicine, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany.
2
University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, 79104 Freiburg, Germany.
3
German Cancer Consortium (DKTK), 79106 Freiburg, Germany.
4
German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
5
Department of General and Visceral Surgery, University of Freiburg Medical Center, Hugstetter Strasse 55, 79106 Freiburg, Germany.
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.
7
Department of Internal Medicine 5, Hematology and Oncology, Universitätsklinikum, FAU University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
8
Department of Radiology Medical Physics, University Medical Center, Freiburg, Breisacher Strasse 60a, 79106 Freiburg, Germany.
9
Institute of Pathology and Comprehensive Cancer Center, University Medical Center, Freiburg, Breisacher Strasse 115a, 79106 Freiburg, Germany.
10
Edinburgh Cancer Research Centre, Institute of Genetics &Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
11
Department of Surgery, Universitätsklinikum, FAU University Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany.
12
Chair of Genetics, Nikolaus-Fiebiger-Center for Molecular Medicine, Department Biology, FAU University Erlangen-Nürnberg, Glückstrasse 6, 91054 Erlangen, Germany.

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.

Comment in

PMID:
28414315
DOI:
10.1038/ncb3513
[Indexed for MEDLINE]

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