NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts

Transforming growth factor beta (TGF-β) signalling has become an attractive therapeutic target due to its pro-tumorigenic actions on epithelial cells and its immunosuppressive effects in the tumour microenvironment. In intrahepatic cholangiocarcinoma (iCCA), a highly aggressive malignancy of the biliary tract with poor prognosis, the latest clinical trials using TGF-β inhibitors have failed indicating that the specific actions carried out by TGF-β in iCCA are yet not well delineated. Here, we show that TGF-β signalling is highly active in iCCA and exerts a prominent suppressor effect on tumour cell lines and organoids established from iCCA metastases biopsies, that relies on a functional canonical SMAD2/3/4 signalling. Thus, TGF-β inhibitors promote, instead of inhibiting, tumour cell growth. In this context, a promising strategy is to target intracellular proteins downstream the TGF-β receptors accounting only for TGF-β pro-tumorigenic actions. NADPH oxidase 4 (NOX4), a downstream mediator of the TGF-β signalling pathway, is strictly expressed in cancer-associated fibroblasts (CAF) of iCCA and acts in concert with NOX1 to regulate CAF functions. Use of a dual NOX4/NOX1 inhibitor impaired CAF actions and reduced tumour growth in vitro and in two different in vivo iCCA experimental models. Collectively, our findings reveal an actionable way to specifically target TGF-β pro-tumorigenic actions in CAF from iCCA without undesirable side effects on tumour cells, suggesting a potentially bright future for dual NOX4/NOX1 inhibitors in the clinics, alone or in combination with other therapies.

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Publication Details

Journal
Signal Transduction and Targeted Therapy
Published
2025-08-17
DOI
https://doi.org/10.1038/s41392-025-02347-z
Citations
4
Primary Topic
Cholangiocarcinoma and Gallbladder Cancer Studies
Type
article
Field-Weighted Citation Impact
8.03
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article

NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts

Sumera I. Ilyas, Emilio Ramos, Josep Amengual, Beatriz Martín‐Mur et al.
4 citations
Signal Transduction and Targeted Therapy
Cholangiocarcinoma and Gallbladder Cancer Studies
8.03
article

NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts

Sumera I. Ilyas, Emilio Ramos, Josep Amengual, Beatriz Martín‐Mur, Anna Esteve‐Codina, Sara Hijazo‐Pechero, Joana Ferrer, Ania Alay, Laura Sererols-Viñas, Alexander Scheiter, Cédric Coulouarn, Marie Vallette, Lynda Aoudjehane, Noel P. Fusté, Rut Espinosa‐Sotelo, Marie Lequoy, Steven Dooley, Tian V. Tian, Ester Gonzalez‐Sanchez, Mariana Yáñez-Bartolomé, Javier Vaquero, Aashreya Ravichandra, Isabel Fabregat, Mariona Calvo, Andrés Méndez‐Lucas, Silvia Affò, Diego F. Calvisi, Berta Laquente, Marta Ortova Gut, Laura Fouassier, Teresa Serrano, Gabriel Pons, Ana Cantos‐Cortes, Celia Guiton
article en
4 citations

Abstract

Transforming growth factor beta (TGF-β) signalling has become an attractive therapeutic target due to its pro-tumorigenic actions on epithelial cells and its immunosuppressive effects in the tumour microenvironment. In intrahepatic cholangiocarcinoma (iCCA), a highly aggressive malignancy of the biliary tract with poor prognosis, the latest clinical trials using TGF-β inhibitors have failed indicating that the specific actions carried out by TGF-β in iCCA are yet not well delineated. Here, we show that TGF-β signalling is highly active in iCCA and exerts a prominent suppressor effect on tumour cell lines and organoids established from iCCA metastases biopsies, that relies on a functional canonical SMAD2/3/4 signalling. Thus, TGF-β inhibitors promote, instead of inhibiting, tumour cell growth. In this context, a promising strategy is to target intracellular proteins downstream the TGF-β receptors accounting only for TGF-β pro-tumorigenic actions. NADPH oxidase 4 (NOX4), a downstream mediator of the TGF-β signalling pathway, is strictly expressed in cancer-associated fibroblasts (CAF) of iCCA and acts in concert with NOX1 to regulate CAF functions. Use of a dual NOX4/NOX1 inhibitor impaired CAF actions and reduced tumour growth in vitro and in two different in vivo iCCA experimental models. Collectively, our findings reveal an actionable way to specifically target TGF-β pro-tumorigenic actions in CAF from iCCA without undesirable side effects on tumour cells, suggesting a potentially bright future for dual NOX4/NOX1 inhibitors in the clinics, alone or in combination with other therapies.

Signal Transduction and Targeted TherapyVol. 10(1)
Délégation Paris 5 (FR), Mayo Clinic (US), Inserm (FR), Universidad de Salamanca (ES), Heidelberg University (DE), Instituto de Salud Carlos III (ES), Bellvitge University Hospital (ES), University Hospital Heidelberg (DE), WinnMed (US), Sorbonne Université (FR), Institut d'Investigació Biomédica de Bellvitge (ES), Oncogenesis Stress Signaling (FR), Assistance Publique – Hôpitaux de Paris (FR), Vall d'Hebron Institut de Recerca (ES), Hôpital Saint-Antoine (FR), Institut Català d'Oncologia (ES), Hospital Clínic de Barcelona (ES), Centre de Recherche Saint-Antoine (FR), Centro de Investigación del Cáncer (ES), Centro Nacional de Análisis Genómico (ES), Fondation pour l’innovation en Cadiométabolisme et Nutrition (FR), University Medical Centre Mannheim (DE), Fundació Clínic per a la Recerca Biomèdica (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Université de Rennes (FR), University of Regensburg (DE), Technical University of Munich (DE), Universitat de Barcelona (ES)
Good health and well-being
Openalex Percentile: Top 2%
Cholangiocarcinoma and Gallbladder Cancer Studies
8.03
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