TY - JOUR
T1 - The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer
AU - Krebs, Angela M.
AU - Mitschke, Julia
AU - Losada, María Lasierra
AU - Schmalhofer, Otto
AU - Boerries, Melanie
AU - Busch, Hauke
AU - Boettcher, Martin
AU - Mougiakakos, DImitrios
AU - Reichardt, Wilfried
AU - Bronsert, Peter
AU - Brunton, Valerie G.
AU - Pilarsky, Christian
AU - Winkler, Thomas H.
AU - Brabletz, Simone
AU - Stemmler, Marc P.
AU - Brabletz, Thomas
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85017499836&partnerID=8YFLogxK
U2 - 10.1038/ncb3513
DO - 10.1038/ncb3513
M3 - Journal articles
C2 - 28414315
AN - SCOPUS:85017499836
SN - 1465-7392
VL - 19
SP - 518
EP - 529
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -
