Role of the EMT activator ZEB1 in pancreatic cancer invasion, dissemination and metastasis
Final Report Abstract
Metastasis is the major cause of cancer-associated death. Partial activation of the epithelial-tomesenchymal transition program (partial EMT) was considered a major driver of tumour progression from initiation to metastasis. However, the role of EMT in promoting tumor progression metastasis has been always challenged, in particular concerning effects of EMT-activating transcription factors (EMT-TFs). The work in our project clearly demonstrated a crucial role of the EMT-TF Zeb1 in a pancreatic cancer metastasis. Using a mouse pancreatic cancer model, driven by the Pdx1-cremediated activation of mutant Kras and p53 (KPC model), we showed that 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. Our data and initial publication of the first results derived from this project created world-wide attention, because it clearly demonstrated a role for EMT in metastasis. In the course of this debate we were invited to write comment, viewpoint and review articles in highest ranked journals discussing and clarifying the dispute about EMT in cancer, which were all highly cited. Moreover, since in the same KPC mouse model the EMT-TFs Snail and Twist did not affect metastasis, but the EMT-TF Zeb1 did, we proposed a non-redundant, context dependent function of EMT-TFs, which was now observed in various processes also by other groups. Our data clearly point out to EMT in general and the EMT-TF Zeb1 in particular as a highly promising therapeutic target to prevent metastasis formation. In summary we consider the project as highly successful. The project resulted in six publications in high ranked journals (three original and three review/opinion articles). Over the years of funding we generated a huge fundus of data, which was the basis for a number of follow-up third party funded projects.
Publications
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(2017). The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol, 19(5):518-529
Krebs, A. M., Mitschke, J., Losada, M. L., Schmalhofer, O., Boerries, M., Busch, H., Boettcher, M., Mougiakakos, D., Reichardt, W., Bronsert, P., Brunton, V. G., Pilarsky, C., Winkler, T. H., Brabletz, S., Stemmler, M. P., Brabletz, T.
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(2017). Upholding a role for EMT in pancreatic cancer metastasis. Nature 547, E7-E8
Aiello NM, Brabletz T, Kang Y, Nieto MA, Weinberg RA, Stanger BZ
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Generation and characterization of mice for conditional inactivation of Zeb1. Genesis 55
Brabletz S, Lasierra Losada M, Schmalhofer O, Mitschke J, Krebs A, Brabletz T, Stemmler MP
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EMT in Cancer. Nat Rev Cancer
Brabletz T, Kalluri R, Nieto MA, Weinberg RA
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(2019). Non-redundant functions of EMT transcription factors. Nat Cell Biol 21:102-112
Stemmler MP, Eccles RL, Brabletz S, Brabletz T
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(2020). Genome-wide cooperation of the EMT-activator ZEB1 with YAP and AP-1 factors in breast cancer. EMBO J, 39(17):e103209
Feldker N, Ferrazzi F, Widholz SA, Guenther K, Lukassen S, Kleemann J, Riegel D, Bönisch U, Eccles RL, Schmidl C, Stemmler MP, Brabletz T, Brabletz S
