Amengual, Josep and Gonzalez-Sanchez, Ester and Yanez-Bartolome, Mariana and Sererols-Vinas, Laura and Ravichandra, Aashreya and Guiton, Celia and Fuste, Noel P. and Alay, Ania and Hijazo-Pechero, Sara and Martin-Mur, Beatriz and Gut, Marta and Esteve-Codina, Anna and Cantos-Cortes, Ana and Espinosa-Sotelo, Rut and Ramos, Emilio and Serrano, Teresa and Calvo, Mariona and Laquente, Berta and Ferrer, Joana and Pons, Gabriel and Mendez-Lucas, Andres and Dooley, Steven and Ilyas, Sumera I. and Vallette, Marie and Aoudjehane, Lynda and Lequoy, Marie and Fouassier, Laura and Coulouarn, Cedric and Affo, Silvia and Scheiter, Alexander and Calvisi, Diego F. and Tian, Tian V. and Fabregat, Isabel and Vaquero, Javier (2025) NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts. SIGNAL TRANSDUCTION AND TARGETED THERAPY, 10 (1): 257. ISSN 2095-9907, 2059-3635
Full text not available from this repository. (Request a copy)Abstract
Transforming growth factor beta (TGF-beta) 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-beta inhibitors have failed indicating that the specific actions carried out by TGF-beta in iCCA are yet not well delineated. Here, we show that TGF-beta 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-beta inhibitors promote, instead of inhibiting, tumour cell growth. In this context, a promising strategy is to target intracellular proteins downstream the TGF-beta receptors accounting only for TGF-beta pro-tumorigenic actions. NADPH oxidase 4 (NOX4), a downstream mediator of the TGF-beta 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-beta 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EXPRESSION; GENE; PROLIFERATION; PROGNOSIS; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2026 13:33 |
| Last Modified: | 24 Mar 2026 13:33 |
| URI: | https://pred.uni-regensburg.de/id/eprint/68050 |
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