Interaction of the EMT-activator ZEB1 and the Yap/Taz/Hippo-pathway in cancer
Hematology, Oncology
Final Report Abstract
Many solid cancers can be successfully removed by surgical resection. However two main clinical problems impede a cure or a long time survival of cancer patients: Metastasis and/or resistance to radio-/chemotherapy. The only option to improve the patients’ situation is the development of novel therapeutic strategies fighting such fatal processes and the basis for that is to uncover the underlying molecular mechanisms. Two cellular programmes/pathways - the epithelial-mesenchymal transition (EMT) and the Hippo-pathway - turned out to play crucial roles. In this project, we determined a direct interaction of these two oncogenic programmes/pathways, which then exert cooperative tumor promoting effects in cancer cells. We have further shown that members of the AP-1 family, another crucial oncogenic transcription factor, integrates in the ZEB1/YAP complex, thus linking downstream effectors of three major oncogenic pathways in a transcriptionally active complex. Importantly recruitment in this complex shifts the function of the EMT-activator ZEB1 from a transcriptional repressor (of tumor-suppressing epithelial genes) into a transcriptional activator (of tumor promoting genes). The presence of ZEB1/YAP/AP-1 as well as identified downstream target gene sets of this complex in cancer cells was associated with highly aggressive subtypes of breast cancer and indicated poor outcome. Thus, our results are of high translational/clinical relevance. Initial experiments indicate that the identified molecular connections and mechanisms are promising targets for novel treatment strategies against aggressive cancer types. In summary, we consider the project as very successful. 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. These include projects in the newly granted SFB/TRR 305, one project funded by the Wilhelm Sander Stiftung, as well a DFG-project just granted for the new SPP 2306.
Publications
- (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.
(See online at https://doi.org/10.1038/ncb3513) - (2017). Upholding a role for EMT in breast cancer metastasis. Nature. 2017 Jul 5;547(7661)
Ye X, Brabletz T, Kang Y, Longmore GD, Nieto MA, Stanger BZ, Yang J, Weinberg RA
(See online at https://doi.org/10.1038/nature22816) - (2017). Upholding a role for EMT in pancreatic cancer metastasis. Nature 547, E7-E8 (communication letter)
Aiello NM, Brabletz T, Kang Y, Nieto MA, Weinberg RA, Stanger BZ
(See online at https://doi.org/10.1038/nature22963) - EMT in Cancer. Nat Rev Cancer
Brabletz T, Kalluri R, Nieto MA, Weinberg RA
(See online at https://doi.org/10.1038/nrc.2017.118) - (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
(See online at https://doi.org/10.15252/embj.2019103209)
