1. ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.
- Author
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Menche C, Schuhwerk H, Armstark I, Gupta P, Fuchs K, van Roey R, Mosa MH, Hartebrodt A, Hajjaj Y, Clavel Ezquerra A, Selvaraju MK, Geppert CI, Bärthel S, Saur D, Greten FR, Brabletz S, Blumenthal DB, Weigert A, Brabletz T, Farin HF, and Stemmler MP
- Subjects
- Animals, Mice, Humans, Gene Expression Regulation, Neoplastic, Fibroblasts metabolism, Cell Line, Tumor, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Epithelial-Mesenchymal Transition genetics, Zinc Finger E-box-Binding Homeobox 1 metabolism, Zinc Finger E-box-Binding Homeobox 1 genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Colorectal Neoplasms therapy, Colorectal Neoplasms immunology, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Inflammation metabolism, Inflammation genetics, Inflammation pathology, Immunotherapy methods
- Abstract
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 are reduced. Single-cell transcriptomics, histological characterization, and in vitro modeling reveal a crucial role of ZEB1 in CAF polarization, promoting myofibroblastic features by restricting inflammatory activation. Zeb1 deficiency impairs collagen deposition and CAF barrier function but increases NFκB-mediated cytokine production, jointly promoting lymphocyte recruitment and immune checkpoint activation. Strikingly, the Zeb1-deficient CAF repertoire sensitizes to immune checkpoint inhibition, offering 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., (© 2024. The Author(s).)
- Published
- 2024
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