Cover Image

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 bil...

Full description

Saved in:
Bibliographic Details
Main Authors: Amengual, Josep (Author) , Gonzalez-Sanchez, Ester (Author) , Yáñez-Bartolome, Mariana (Author) , Sererols-Viñas, Laura (Author) , Ravichandra, Aashreya (Author) , Guiton, Celia (Author) , Fuste, Noel P. (Author) , Alay, Ania (Author) , Hijazo-Pechero, Sara (Author) , Martín-Mur, Beatriz (Author) , Gut, Marta (Author) , Esteve-Codina, Anna (Author) , Cantos-Cortes, Ana (Author) , Espinosa-Sotelo, Rut (Author) , Ramos, Emilio (Author) , Serrano, Teresa (Author) , Calvo, Mariona (Author) , Laquente, Berta (Author) , Ferrer, Joana (Author) , Pons, Gabriel (Author) , Mendez-Lucas, Andrés (Author) , Dooley, Steven (Author) , Ilyas, Sumera I. (Author) , Vallette, Marie (Author) , Aoudjehane, Lynda (Author) , Lequoy, Marie (Author) , Fouassier, Laura (Author) , Coulouarn, Cédric (Author) , Affò, Silvia (Author) , Scheiter, Alexander (Author) , Calvisi, Diego F. (Author) , Tian, Tian V. (Author) , Fabregat, Isabel (Author) , Vaquero, Javier (Author)
Format: Article (Journal)
Language:English
Published: 18 August 2025
In: Signal transduction and targeted therapy
Year: 2025, Volume: 10, Pages: 1-21
ISSN:2059-3635
DOI:10.1038/s41392-025-02347-z
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41392-025-02347-z
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41392-025-02347-z
Get full text
Author Notes:Josep Amengual, Ester Gonzalez-Sanchez, Mariana Yáñez-Bartolome, Laura Sererols-Viñas, Aashreya Ravichandra, Celia Guiton, Noel P. Fuste, Ania Alay, Sara Hijazo-Pechero, Beatriz Martín-Mur, Marta Gut, Anna Esteve-Codina, Ana Cantos-Cortes, Rut Espinosa-Sotelo, Emilio Ramos, Teresa Serrano, Mariona Calvo, Berta Laquente, Joana Ferrer, Gabriel Pons, Andrés Mendez-Lucas, Steven Dooley, Sumera I. Ilyas, Marie Vallette, Lynda Aoudjehane, Marie Lequoy, Laura Fouassier, Cédric Coulouarn, Silvia Affò, Alexander Scheiter, Diego F. Calvisi, Tian V. Tian, Isabel Fabregat and Javier Vaquero

MARC

LEADER 00000naa a2200000 c 4500
001 1940742676
003 DE-627
005 20251110133239.0
007 cr uuu---uuuuu
008 251110s2025 xx |||||o 00| ||eng c
024 7 |a 10.1038/s41392-025-02347-z  |2 doi 
035 |a (DE-627)1940742676 
035 |a (DE-599)KXP1940742676 
040 |a DE-627  |b ger  |c DE-627  |e rda 
041 |a eng 
084 |a 33  |2 sdnb 
100 1 |a Amengual, Josep  |e VerfasserIn  |0 (DE-588)1381201946  |0 (DE-627)1940743303  |4 aut 
245 1 0 |a NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts  |c Josep Amengual, Ester Gonzalez-Sanchez, Mariana Yáñez-Bartolome, Laura Sererols-Viñas, Aashreya Ravichandra, Celia Guiton, Noel P. Fuste, Ania Alay, Sara Hijazo-Pechero, Beatriz Martín-Mur, Marta Gut, Anna Esteve-Codina, Ana Cantos-Cortes, Rut Espinosa-Sotelo, Emilio Ramos, Teresa Serrano, Mariona Calvo, Berta Laquente, Joana Ferrer, Gabriel Pons, Andrés Mendez-Lucas, Steven Dooley, Sumera I. Ilyas, Marie Vallette, Lynda Aoudjehane, Marie Lequoy, Laura Fouassier, Cédric Coulouarn, Silvia Affò, Alexander Scheiter, Diego F. Calvisi, Tian V. Tian, Isabel Fabregat and Javier Vaquero 
264 1 |c 18 August 2025 
300 |b Illustrationen, Diagramme 
300 |a 21 
336 |a Text  |b txt  |2 rdacontent 
337 |a Computermedien  |b c  |2 rdamedia 
338 |a Online-Ressource  |b cr  |2 rdacarrier 
500 |a Gesehen am 10.11.2025 
520 |a 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. 
650 4 |a Cancer microenvironment 
650 4 |a Cancer therapy 
650 4 |a Target identification 
700 1 |a Gonzalez-Sanchez, Ester  |e VerfasserIn  |4 aut 
700 1 |a Yáñez-Bartolome, Mariana  |e VerfasserIn  |4 aut 
700 1 |a Sererols-Viñas, Laura  |e VerfasserIn  |4 aut 
700 1 |a Ravichandra, Aashreya  |e VerfasserIn  |4 aut 
700 1 |a Guiton, Celia  |e VerfasserIn  |4 aut 
700 1 |a Fuste, Noel P.  |e VerfasserIn  |4 aut 
700 1 |a Alay, Ania  |e VerfasserIn  |4 aut 
700 1 |a Hijazo-Pechero, Sara  |e VerfasserIn  |4 aut 
700 1 |a Martín-Mur, Beatriz  |e VerfasserIn  |4 aut 
700 1 |a Gut, Marta  |e VerfasserIn  |4 aut 
700 1 |a Esteve-Codina, Anna  |e VerfasserIn  |4 aut 
700 1 |a Cantos-Cortes, Ana  |e VerfasserIn  |4 aut 
700 1 |a Espinosa-Sotelo, Rut  |e VerfasserIn  |4 aut 
700 1 |a Ramos, Emilio  |e VerfasserIn  |4 aut 
700 1 |a Serrano, Teresa  |e VerfasserIn  |4 aut 
700 1 |a Calvo, Mariona  |e VerfasserIn  |4 aut 
700 1 |a Laquente, Berta  |e VerfasserIn  |4 aut 
700 1 |a Ferrer, Joana  |e VerfasserIn  |4 aut 
700 1 |a Pons, Gabriel  |e VerfasserIn  |4 aut 
700 1 |a Mendez-Lucas, Andrés  |e VerfasserIn  |4 aut 
700 1 |a Dooley, Steven  |d 1960-  |e VerfasserIn  |0 (DE-588)1028589190  |0 (DE-627)73128951X  |0 (DE-576)376074116  |4 aut 
700 1 |a Ilyas, Sumera I.  |e VerfasserIn  |4 aut 
700 1 |a Vallette, Marie  |e VerfasserIn  |4 aut 
700 1 |a Aoudjehane, Lynda  |e VerfasserIn  |4 aut 
700 1 |a Lequoy, Marie  |e VerfasserIn  |4 aut 
700 1 |a Fouassier, Laura  |e VerfasserIn  |4 aut 
700 1 |a Coulouarn, Cédric  |e VerfasserIn  |4 aut 
700 1 |a Affò, Silvia  |e VerfasserIn  |4 aut 
700 1 |a Scheiter, Alexander  |e VerfasserIn  |4 aut 
700 1 |a Calvisi, Diego F.  |e VerfasserIn  |4 aut 
700 1 |a Tian, Tian V.  |e VerfasserIn  |4 aut 
700 1 |a Fabregat, Isabel  |e VerfasserIn  |4 aut 
700 1 |a Vaquero, Javier  |e VerfasserIn  |4 aut 
773 0 8 |i Enthalten in  |t Signal transduction and targeted therapy  |d London : Macmillan Publishers, part of Springer Nature, 2016  |g 10(2025), Artikel-ID 257, Seite 1-21  |h Online-Ressource  |w (DE-627)881466581  |w (DE-600)2886872-9  |w (DE-576)484899252  |x 2059-3635  |7 nnas  |a NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts 
773 1 8 |g volume:10  |g year:2025  |g elocationid:257  |g pages:1-21  |g extent:21  |a NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts 
856 4 0 |u https://doi.org/10.1038/s41392-025-02347-z  |x Verlag  |x Resolving-System  |z kostenfrei  |3 Volltext 
856 4 0 |u https://www.nature.com/articles/s41392-025-02347-z  |x Verlag  |z kostenfrei  |3 Volltext 
951 |a AR 
992 |a 20251110 
993 |a Article 
994 |a 2025 
998 |g 1028589190  |a Dooley, Steven  |m 1028589190:Dooley, Steven  |d 60000  |d 61100  |e 60000PD1028589190  |e 61100PD1028589190  |k 0/60000/  |k 1/60000/61100/  |p 22 
999 |a KXP-PPN1940742676  |e 4801866360 
BIB |a Y 
SER |a journal 
JSO |a {"language":["eng"],"person":[{"family":"Amengual","given":"Josep","display":"Amengual, Josep","role":"aut"},{"family":"Gonzalez-Sanchez","given":"Ester","display":"Gonzalez-Sanchez, Ester","role":"aut"},{"given":"Mariana","family":"Yáñez-Bartolome","role":"aut","display":"Yáñez-Bartolome, Mariana"},{"role":"aut","display":"Sererols-Viñas, Laura","given":"Laura","family":"Sererols-Viñas"},{"given":"Aashreya","family":"Ravichandra","role":"aut","display":"Ravichandra, Aashreya"},{"display":"Guiton, Celia","role":"aut","family":"Guiton","given":"Celia"},{"display":"Fuste, Noel P.","role":"aut","family":"Fuste","given":"Noel P."},{"family":"Alay","given":"Ania","display":"Alay, Ania","role":"aut"},{"role":"aut","display":"Hijazo-Pechero, Sara","given":"Sara","family":"Hijazo-Pechero"},{"display":"Martín-Mur, Beatriz","role":"aut","family":"Martín-Mur","given":"Beatriz"},{"role":"aut","display":"Gut, Marta","given":"Marta","family":"Gut"},{"display":"Esteve-Codina, Anna","role":"aut","family":"Esteve-Codina","given":"Anna"},{"given":"Ana","family":"Cantos-Cortes","role":"aut","display":"Cantos-Cortes, Ana"},{"role":"aut","display":"Espinosa-Sotelo, Rut","given":"Rut","family":"Espinosa-Sotelo"},{"family":"Ramos","given":"Emilio","display":"Ramos, Emilio","role":"aut"},{"role":"aut","display":"Serrano, Teresa","given":"Teresa","family":"Serrano"},{"family":"Calvo","given":"Mariona","display":"Calvo, Mariona","role":"aut"},{"family":"Laquente","given":"Berta","display":"Laquente, Berta","role":"aut"},{"family":"Ferrer","given":"Joana","display":"Ferrer, Joana","role":"aut"},{"role":"aut","display":"Pons, Gabriel","given":"Gabriel","family":"Pons"},{"family":"Mendez-Lucas","given":"Andrés","display":"Mendez-Lucas, Andrés","role":"aut"},{"given":"Steven","family":"Dooley","role":"aut","display":"Dooley, Steven"},{"role":"aut","display":"Ilyas, Sumera I.","given":"Sumera I.","family":"Ilyas"},{"display":"Vallette, Marie","role":"aut","family":"Vallette","given":"Marie"},{"display":"Aoudjehane, Lynda","role":"aut","family":"Aoudjehane","given":"Lynda"},{"given":"Marie","family":"Lequoy","role":"aut","display":"Lequoy, Marie"},{"family":"Fouassier","given":"Laura","display":"Fouassier, Laura","role":"aut"},{"display":"Coulouarn, Cédric","role":"aut","family":"Coulouarn","given":"Cédric"},{"display":"Affò, Silvia","role":"aut","family":"Affò","given":"Silvia"},{"display":"Scheiter, Alexander","role":"aut","family":"Scheiter","given":"Alexander"},{"display":"Calvisi, Diego F.","role":"aut","family":"Calvisi","given":"Diego F."},{"family":"Tian","given":"Tian V.","display":"Tian, Tian V.","role":"aut"},{"display":"Fabregat, Isabel","role":"aut","family":"Fabregat","given":"Isabel"},{"role":"aut","display":"Vaquero, Javier","given":"Javier","family":"Vaquero"}],"physDesc":[{"noteIll":"Illustrationen, Diagramme","extent":"21 S."}],"type":{"media":"Online-Ressource","bibl":"article-journal"},"id":{"eki":["1940742676"],"doi":["10.1038/s41392-025-02347-z"]},"title":[{"title":"NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts","title_sort":"NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblasts"}],"relHost":[{"note":["Gesehen am 24 August 2020"],"disp":"NADPH oxidase 1/4 dual inhibition impairs transforming growth factor-beta protumorigenic effects in cholangiocarcinoma cancer-associated fibroblastsSignal transduction and targeted therapy","language":["eng"],"physDesc":[{"extent":"Online-Ressource"}],"title":[{"title_sort":"Signal transduction and targeted therapy","title":"Signal transduction and targeted therapy"}],"recId":"881466581","origin":[{"dateIssuedDisp":"[2016]-","publisher":"Macmillan Publishers, part of Springer Nature","publisherPlace":"London"}],"type":{"media":"Online-Ressource","bibl":"periodical"},"id":{"eki":["881466581"],"zdb":["2886872-9"],"issn":["2059-3635"]},"pubHistory":["28 January 2016-"],"part":{"text":"10(2025), Artikel-ID 257, Seite 1-21","pages":"1-21","extent":"21","year":"2025","volume":"10"}}],"name":{"displayForm":["Josep Amengual, Ester Gonzalez-Sanchez, Mariana Yáñez-Bartolome, Laura Sererols-Viñas, Aashreya Ravichandra, Celia Guiton, Noel P. Fuste, Ania Alay, Sara Hijazo-Pechero, Beatriz Martín-Mur, Marta Gut, Anna Esteve-Codina, Ana Cantos-Cortes, Rut Espinosa-Sotelo, Emilio Ramos, Teresa Serrano, Mariona Calvo, Berta Laquente, Joana Ferrer, Gabriel Pons, Andrés Mendez-Lucas, Steven Dooley, Sumera I. Ilyas, Marie Vallette, Lynda Aoudjehane, Marie Lequoy, Laura Fouassier, Cédric Coulouarn, Silvia Affò, Alexander Scheiter, Diego F. Calvisi, Tian V. Tian, Isabel Fabregat and Javier Vaquero"]},"recId":"1940742676","note":["Gesehen am 10.11.2025"],"origin":[{"dateIssuedKey":"2025","dateIssuedDisp":"18 August 2025"}]} 
SRT |a AMENGUALJONADPHOXIDA1820 

Similar Items