| First Author | Menche C | Year | 2024 |
| Journal | EMBO Rep | Volume | 25 |
| Issue | 8 | Pages | 3406-3431 |
| PubMed ID | 38937629 | Mgi Jnum | J:353295 |
| Mgi Id | MGI:7710817 | Doi | 10.1038/s44319-024-00186-7 |
| Citation | Menche C, et al. (2024) ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer. EMBO Rep 25(8):3406-3431 |
| abstractText | 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 NFkappaB-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. |
