@article{0f70ba73a74544b4947e7ba1993d7a15,
title = "The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response",
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.",
keywords = "cancer, cell cycle, chemoresistance, CP: Cancer, DNA damage response, DNA replication stress, epithelial-to-mesenchymal transition, heterogeneity, MRE11, plasticity, ZEB1",
author = "Harald Schuhwerk and Julia Kleemann and Pooja Gupta and \{van Roey\}, Ruthger and Isabell Armstark and Martina Kreileder and Nora Feldker and Vignesh Ramesh and Yussuf Hajjaj and Kathrin Fuchs and Mousumi Mahapatro and Mojca Hribersek and Marco Volante and Arwin Groenewoud and Engel, \{Felix B.\} and Paolo Ceppi and Markus Eckstein and Arndt Hartmann and Fabian M{\"u}ller and Torsten Kroll and Stemmler, \{Marc P.\} and Simone Brabletz and Thomas Brabletz",
note = "Funding Information: We are grateful for Eva Bauer, Britta Schlund, and Friederike Gr{\"a}bner for excellent technical assistance in the laboratory. We thank Uwe Appelt and Markus Mroz for excellent fluorescence-activated cell sorting (FACS) support. This work was supported by grants to S.B. and H.S. as well as F.B.E. from the Wilhelm Sander-Stiftung (2020.039.1; 2019.143.1); to T.B., S.B., M.P.S., and F.B.E. from the German Research Foundation ( FOR2438/P04 ; TRR305/A03 , A04 , B07 , and the Priority Programme SPP 2084 , EN 453/13-1 ); and to M.P.S. from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 861196 (PRECODE). Funding Information: We are grateful for Eva Bauer, Britta Schlund, and Friederike Gr{\"a}bner for excellent technical assistance in the laboratory. We thank Uwe Appelt and Markus Mroz for excellent fluorescence-activated cell sorting (FACS) support. This work was supported by grants to S.B. and H.S. as well as F.B.E. from the Wilhelm Sander-Stiftung (2020.039.1; 2019.143.1); to T.B. S.B. M.P.S. and F.B.E. from the German Research Foundation (FOR2438/P04; TRR305/A03, A04, B07, and the Priority Programme SPP 2084, EN 453/13-1); and to M.P.S. from the European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 861196 (PRECODE). Conceptualization, H.S. S.B. and T.B.; methodology and validation, H.S. J.K. P.G. M.P.S. P.C. and T.K.; software, H.S. J.K. P.G. R.v.R. N.F. and V.R.; formal analysis, H.S. J.K. R.v.R. P.G. M.V. N.F. Y.H. and V.R.; investigation, H.S. J.K. I.A. M.K. K.F. M.M. M.H. and A.G.; resources, M.V. M.E. A.H. Y.H. N.F. R.v.R. F.M. and F.B.E.; writing – original draft, H.S. and J.K.; writing – review \& editing, H.S. J.K. T.K. S.B. T.B. and M.P.S.; supervision, H.S. T.B. and S.B.; funding acquisition, H.S. S.B. T.B. and M.P.S. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = dec,
day = "13",
doi = "10.1016/j.celrep.2022.111819",
language = "English",
volume = "41",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}