Amengual Josep, Gonzalez-Sanchez Ester, Yáñez-Bartolome Mariana, Sererols-Viñas Laura, Ravichandra Aashreya, Guiton Celia, Fuste Noel P, Alay Ania, Hijazo-Pechero Sara, Martín-Mur Beatriz, Gut Marta, Esteve-Codina Anna, Cantos-Cortes Ana, Espinosa-Sotelo Rut, Ramos Emilio, Serrano Teresa, Calvo Mariona, Laquente Berta, Ferrer Joana, Pons Gabriel, Mendez-Lucas Andrés, Dooley Steven, Ilyas Sumera I, Vallette Marie, Aoudjehane Lynda, Lequoy Marie, Fouassier Laura, Coulouarn Cédric, Affò Silvia, Scheiter Alexander, Calvisi Diego F, Tian Tian V, Fabregat Isabel, Vaquero Javier
TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
CIBEREHD, National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III, Madrid, Spain.
Signal Transduct Target Ther. 2025 Aug 18;10(1):257. doi: 10.1038/s41392-025-02347-z.
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.
转化生长因子β（TGF-β）信号传导已成为一个有吸引力的治疗靶点，因为它对上皮细胞具有促肿瘤作用，并且在肿瘤微环境中具有免疫抑制作用。在肝内胆管癌（iCCA）中，这是一种侵袭性很强、预后很差的胆道恶性肿瘤，使用TGF-β抑制剂的最新临床试验失败了，这表明TGF-β在iCCA中所发挥的具体作用尚未得到很好的描述。在这里，我们表明TGF-β信号传导在iCCA中高度活跃，并对从iCCA转移活检中建立的肿瘤细胞系和类器官发挥显著的抑制作用，这依赖于功能性的经典SMAD2/3/4信号传导。因此，TGF-β抑制剂促进而不是抑制肿瘤细胞生长。在这种情况下，一种有前景的策略是靶向TGF-β受体下游仅负责TGF-β促肿瘤作用的细胞内蛋白。NADPH氧化酶4（NOX4）是TGF-β信号通路的下游介质，在iCCA的癌症相关成纤维细胞（CAF）中严格表达，并与NOX1协同作用来调节CAF的功能。使用双NOX4/NOX1抑制剂会损害CAF的作用，并在体外和两种不同的体内iCCA实验模型中降低肿瘤生长。总的来说，我们的研究结果揭示了一种可操作的方法，能够特异性地靶向iCCA中CAF的TGF-β促肿瘤作用，而不会对肿瘤细胞产生不良副作用，这表明双NOX4/NOX1抑制剂在临床上单独使用或与其他疗法联合使用可能具有光明的前景。
