The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response.

Mojca Hribersek, Thomas Brabletz, Simone Brabletz, Marc P Stemmler, Torsten Kroll, Fabian Müller, Arndt Hartmann, Markus Eckstein, Paolo Ceppi, Felix B Engel, Arwin Groenewoud, Marco Volante, Harald Schuhwerk, Mousumi Mahapatro, Kathrin Fuchs, Yussuf Hajjaj, Vignesh Ramesh, Nora Feldker, Martina Kreileder, Isabell Armstark, Ruthger van Roey, Pooja Gupta, Julia Kleemann

Journal: Cell reports 2022;41(11):111819

PMID: 36516781

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Abstract

The DNA damage response (DDR) and epithelial-to-mesenchymal transition (EMT) are two crucial cellular programs in cancer biology. While the DDR orchestrates cell-cycle progression, DNA repair, and cell death, EMT promotes invasiveness, cellular plasticity, and intratumor heterogeneity. Therapeutic targeting of EMT transcription factors, such as ZEB1, remains challenging, but tumor-promoting DDR alterations elicit specific vulnerabilities. Using multi-omics, inhibitors, and high-content microscopy, we discover a chemoresistant ZEB1-high-expressing sub-population (ZEB1) with co-rewired cell-cycle progression and proficient DDR across tumor entities. ZEB1 stimulates accelerated S-phase entry via CDK6, inflicting endogenous DNA replication stress. However, DDR buildups involving constitutive MRE11-dependent fork resection allow homeostatic cycling and enrichment of ZEB1 cells during transforming growth factor β (TGF-β)-induced EMT and chemotherapy. Thus, ZEB1 promotes G1/S transition to launch a progressive DDR benefitting stress tolerance, which concurrently manifests a targetable vulnerability in chemoresistant ZEB1 cells. Our study thus highlights the translationally relevant intercept of the DDR and EMT.

Address: Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].; Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.; Core Unit for Bioinformatics, Data Integration and Analysis, Center for Medical Information and Communication Technology, University Hospital Erlangen, Erlangen Germany.; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark.; Department of Oncology, University of Turin, Orbassano, Turin, Italy.; Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.; Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen- Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.; Department of Internal Medicine 5, Haematology and Oncology, University Hospital Erlangen, Erlangen Germany.; Leibniz Institute on Aging - Fritz-Lipmann Institute (FLI), Jena, Germany.; Department of Experimental Medicine 1, Nikolaus-Fiebiger Center for Molecular Medicine, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2022.111819

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MeSH Terms: Transcription Factors, Zinc Finger E-box-Binding Homeobox 1, Cell Line, Tumor, Epithelial-Mesenchymal Transition, DNA Replication