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 ...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-βinhibitors have failed indicating that the specific actions carried out by TGF-βin iCCA are yet not well delineated.Here,we show that TGF-βsignalling 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-βinhibitors promote,instead of inhibiting,tumour cell growth.In this context,a promising strategy is to target intracellular proteins downstream the TGF-βreceptors accounting only for TGF-βpro-tumorigenic actions.NADPH oxidase 4(NOX4),a downstream mediator of the TGF-βsignalling 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-βpro-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.展开更多
基金supported by Spanish Association for Cancer Research(AECC),Spain,grant#PRYGN211279FABR,to I.F.Agencia Estatal de Investigación(AEI),Ministry of Science and Innovation(MICIN),Spain,cofounded by FEDER funds/Development Fund—a way to build Europe,grant numbers#RTI2018-094079-B-100,#RTC2019-007125-1,to I.F.+12 种基金#PID2019-108651RJ-I00,PID2022-141984OB-I00 and RYC2021-034121-I,to J.V.J.V.funded by AEI,MICIN,through the Retos Investigación grant number PID2019-108651RJ-I00/DOI 10.13039/501100011033 and“Ramon y Cajal”program RYC2021-034121-IThe CIBEREHD,National Biomedical Research Institute on Liver and Gastrointestinal Diseases,is funded by the Instituto de Salud Carlos III,Spainsupported by Inserm,Universitéde Rennes,Ligue Contre le Cancer(R23037NN),INCa(EU TRANSCAN23-002-2023-129,INCa_18688,R21251ND)ITMO Cancer of AVIESAN within the framework of the 2021-2030 Cancer Control Strategy,on funds administered by Inserm(C18007NS,C20013NS,C20014NS)the French Ministry of Health and the French National Cancer Institute(PRT-K20-136)supported by grants from the Spanish Ministry of Science,Innovation and University(PID2019-108008RJ-I00,PID2023-146827OB-I00),FundacióLa MaratóTV3(201931-31)“Ramon y Cajal”program(RYC2020-029098-I)financial support from the“Ligue contre le cancer”(RS24/75-62)from ITMO Cancer of Aviesan on funds administered by Inserm(C21044DS/ASC21044DSA)supported by PID2021-124694OA-I00,MCIN/AEI/10.13039/501100011033FEDER Una manera de hacer Europa,The European Union grant agreement 101077312*Ramon y Cajal program RYC2022-036321-I.
文摘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-βinhibitors have failed indicating that the specific actions carried out by TGF-βin iCCA are yet not well delineated.Here,we show that TGF-βsignalling 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-βinhibitors promote,instead of inhibiting,tumour cell growth.In this context,a promising strategy is to target intracellular proteins downstream the TGF-βreceptors accounting only for TGF-βpro-tumorigenic actions.NADPH oxidase 4(NOX4),a downstream mediator of the TGF-βsignalling 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-βpro-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.
