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

AM Krebs, J Mitschke, M Lasierra Losada… - Nature cell …, 2017 - nature.com
AM Krebs, J Mitschke, M Lasierra Losada, O Schmalhofer, M Boerries, H Busch, M Boettcher
Nature cell biology, 2017nature.com
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 …
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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