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

Schuhwerk H, Kleemann J, Gupta P, van Roey R, Armstark I, Kreileder M, Feldker N, Ramesh V, Hajjaj Y, Fuchs K, Mahapatro M, Hribersek M, Volante M, Groenewoud A, Engel F, Ceppi P, Eckstein M, Hartmann A, Müller F, Kroll T, Stemmler M, Brabletz S, Brabletz T (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Cell Reports Elsevier (Cell Press)

Book Volume: 41

Journal Issue: 11

DOI: 10.1016/j.celrep.2022.111819

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 (ZEB1hi) 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 ZEB1hi 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 ZEB1hi cells. Our study thus highlights the translationally relevant intercept of the DDR and EMT.

Authors with CRIS profile

Harald Schuhwerk Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Julia Kleemann Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Ruthgerus van Roey Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Isabell Armstark Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Nora Feldker Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Yussuf Hajjaj Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Kathrin Fuchs Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Mousumi Mahapatro Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Arwin Groenewoud Department of Nephropathology Felix Engel Professur für Experimentelle Nieren- und Kreislaufforschung Markus Eckstein Institute of Pathology Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Fabian Müller Department of Medicine 5 – Haematology and Oncology Marc Stemmler Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung Simone Brabletz Lehrstuhl für Experimentelle Medizin II (Molekulare Tumorforschung) Thomas Brabletz Lehrstuhl für Experimentelle Medizin mit dem Schwerpunkt Molekulare Pathogeneseforschung

Involved external institutions

University of Southern Denmark / Syddansk Universitet DK Denmark (DK) University of Turin / Università degli Studi di Torino (UNITO) IT Italy (IT) Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut (FLI) DE Germany (DE)

How to cite

APA:

Schuhwerk, H., Kleemann, J., Gupta, P., van Roey, R., Armstark, I., Kreileder, M.,... Brabletz, T. (2022). The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response. Cell Reports, 41(11). https://dx.doi.org/10.1016/j.celrep.2022.111819

MLA:

Schuhwerk, Harald, et al. "The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response." Cell Reports 41.11 (2022).

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