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. 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

Angela M Krebs  1   2   3   4 , Julia Mitschke  5 , María Lasierra Losada  1 , Otto Schmalhofer  5 , Melanie Boerries  3   4   6 , Hauke Busch  3   4   6 , Martin Boettcher  7 , Dimitrios Mougiakakos  7 , Wilfried Reichardt  3   4   8 , Peter Bronsert  3   4   9 , Valerie G Brunton  10 , Christian Pilarsky  11 , Thomas H Winkler  12 , Simone Brabletz  1 , Marc P Stemmler  1 , Thomas Brabletz  1
Affiliations

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

Angela M Krebs et al. Nat Cell Biol. 2017 May.

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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