ZEB1-mediated fibroblast polarization controls inflammation and sensitivity to immunotherapy in colorectal cancer.
Cancer-Associated Fibroblast Plasticity
Colorectal Cancer
Immune Checkpoint Blockade
Tumor Microenvironment
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
27 Jun 2024
27 Jun 2024
Historique:
received:
16
04
2024
accepted:
13
06
2024
revised:
10
06
2024
medline:
28
6
2024
pubmed:
28
6
2024
entrez:
27
6
2024
Statut:
aheadofprint
Résumé
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.
Identifiants
pubmed: 38937629
doi: 10.1038/s44319-024-00186-7
pii: 10.1038/s44319-024-00186-7
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : FOR2438/P04
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : TRR305 TP A03
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : TRR305 TP A04
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : TRR305 TP B01
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : TRR305 TP B07
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : BR1399/9-1,BR1399/10-1,BR1399/15-1,BR1399/17-1
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : BR4145/1-1,BR4145/2-1,BR4145/3-1
Organisme : Wilhelm Sander-Stiftung (Wilhelm Sander Foundation)
ID : 2020.039.1
Organisme : Interdisziplinaeres Zentrum fuer Klinische Forschung, FAU-Erlangen
ID : IZKF P34,P133 and D39
Organisme : EC | Horizon 2020 Framework Programme (H2020)
ID : No. 861196,PRECODE
Organisme : Bundesministerium für Bildung und Forschung (BMBF)
ID : CompLS [031L0309A (NetMap)]
Informations de copyright
© 2024. The Author(s).
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