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

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

doi:10.1016/j.celrep.2022.111819

Cited by 5 publications

(13 citation statements)

References 94 publications

(161 reference statements)

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“…Previously, a study confirmed that CLL epithelial-mesenchymal transition (EMT) and DDR signaling are part of a negative feedback loop. EMT transcription factors can downregulate p53 activity to suppress DDR and the reverse can occur [ 22 ]. Perhaps our observations confirm that this feedback loop may exist within CLL cell biology as most of the CLL patients had normal/above normal levels of DDR protein activity.…”

Section: Discussionmentioning

confidence: 99%

“…Loading control and topographical normalization procedures were performed to account for protein concentration and background staining variations. The data were normalized by subtracting the median of the rows and columns across all samples to ensure that sample protein expression estimated from different slides could be compared [ 22 ]. Lastly, the median of CD19 control proteins was subtracted to normalize values to a normal median of zero enabling recognition of whether expression in the patient was within, above, or below that of the normal.…”

Section: Methodsmentioning

confidence: 99%

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Prognostication of DNA Damage Response Protein Expression Patterns in Chronic Lymphocytic Leukemia

Griffen

Hoff

Qiu

et al. 2023

IJMS

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Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival outcomes. Patients within clusters C1 and C2 had poorer survival outcomes and responses to fludarabine, cyclophosphamide, and rituxan chemotherapy compared to patients within cluster C3. However, DDR protein expression patterns were not prognostic in more modern therapies with BCL2 inhibitors or a BTK/PI3K inhibitor. Individually, nine of the DDR proteins were prognostic for predicting overall survival and/or time to first treatment. When looking for other proteins that may be associated with or influenced by DDR expression patterns, our differential expression analysis found that cell cycle and adhesion proteins were lower in clusters compared to normal CD19 controls. In addition, cluster C3 had a lower expression of MAPK proteins compared to the poor prognostic patient clusters thus implying a potential regulatory connection between adhesion, cell cycle, MAPK, and DDR signaling in CLL. Thus, assessing the proteomic expression of DNA damage proteins in CLL provided novel insights for deciphering influences on patient outcomes and expanded our understanding of the potential complexities and effects of DDR cell signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prognostication of DNA Damage Response Protein Expression Patterns in Chronic Lymphocytic Leukemia

Griffen

Hoff

Qiu

et al. 2023

IJMS

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“…We furthermore identified ZEB1 as an important regulator of balancing myofibroblastic and inflammatory functions of CRC CAFs. Of note, TGFβ signaling has been shown to be essential for acquisition of classical myofibroblast phenotypes 6,10,12,13,42 and in tumor cells, ZEB1 is a key mediator of TGFβ signaling 19,21,27,43 . This indicates that ZEB1 may act as a mediator of TGFβ signaling during myofibroblast polarization.…”

Section: Discussionmentioning

confidence: 99%

“…Because targeting ZEB1 as a TF is challenging, new strategies will be required. In this regard, we recently discovered an actionable vulnerability in ZEB1 high cancer cell sub-populations by inhibiting the DNA damage response (DDR) nuclease MRE11 43 . Along that line, such selective pharmacological approaches or development of specific PROTACs bear the promise for targeting ZEB1 in CAFs directly or indirectly.…”

Section: Discussionmentioning

confidence: 99%

“…Protein extraction and western blotting was carried out as described (Lehmann et al, 2016, Schuhwerk et al, 2022). Briefly, cells grown in 6 well-plates were lysed in 150 mM NaCl, 50 mM Tris-HCl pH 8.0, 0.5 % Na-Desoxycholate (w/v), 0.1 % SDS (w/v), 1 % NP40 (v/v), 1x complete protease inhibitor (Roche, 4693132001), 1 mM PMSF, 1x PhosSTOP (Roche, 4906837001) for 20 min at 4 °C.…”

Section: Western Blot Analysismentioning

confidence: 99%

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ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer

Schuhwerk¹,

Menche

Armstark³

et al. 2023

Preprint

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The EMT-transcription factor ZEB1 is heterogeneously expressed in tumor cells and in cancer-associated fibroblasts (CAFs) in colorectal cancer (CRC). While ZEB1 in tumor cells regulates metastasis and therapy resistance, its role in CAFs is largely unknown. Combining fibroblast-specific Zeb1 deletion with immunocompetent mouse models of CRC, we observe that inflammation-driven tumorigenesis is accelerated, whereas invasion and metastasis in sporadic cancers is reduced upon fibroblast-specific loss of Zeb1. Single-cell transcriptomics, histological and in vitro characterization reveal a crucial role in CAF polarization, promoting myofibroblastic features whilst restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, pointing to a therapeutic opportunity of targeting ZEB1 in CAFs and its usage as a prognostic biomarker. Collectively, we demonstrate that ZEB1-dependent plasticity of CAFs suppresses anti-tumor immunity and promotes metastasis.

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Mutual regulation of TGFβ-induced oncogenic EMT, cell cycle progression and the DDR

Schuhwerk,

Brabletz

2023

Seminars in Cancer Biology

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

Cited by 5 publications

References 94 publications

Prognostication of DNA Damage Response Protein Expression Patterns in Chronic Lymphocytic Leukemia

Prognostication of DNA Damage Response Protein Expression Patterns in Chronic Lymphocytic Leukemia

ZEB1-dependent modulation of fibroblast polarization governs inflammation and immune checkpoint blockade sensitivity in colorectal cancer

Mutual regulation of TGFβ-induced oncogenic EMT, cell cycle progression and the DDR

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