Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/218004
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dc.contributor.authorTeixido, Cristina-
dc.contributor.authorFernández Nogueira, Patricia-
dc.contributor.authorGalbis, José Marcelo-
dc.contributor.authorAlcaraz, Jordi-
dc.contributor.authorDuch, Paula-
dc.contributor.authorDíaz Valdivia, Natalia-
dc.contributor.authorGabasa Ferràndez, Marta-
dc.contributor.authorIkemori, Rafael-
dc.contributor.authorArshakyan, Marselina-
dc.contributor.authorLlorente, Alejandro-
dc.contributor.authorRamírez, Josep-
dc.contributor.authorPereda, Javier-
dc.contributor.authorChuliá Peris, Lourdes-
dc.contributor.authorHilberg, Frank-
dc.contributor.authorReguart, Noemí-
dc.contributor.authorRadisky, Derek C-
dc.contributor.authorAlcaraz, Jordi-
dc.date.accessioned2025-01-27T14:05:01Z-
dc.date.available2025-01-27T14:05:01Z-
dc.date.issued2024-03-12-
dc.identifier.issn1347-9032-
dc.identifier.urihttps://hdl.handle.net/2445/218004-
dc.description.abstractThe fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with in vitro and in vivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.-
dc.format.extent15 p.-
dc.format.mimetypeapplication/pdf-
dc.language.isoeng-
dc.publisherWiley-
dc.relation.isformatofReproducció del document publicat a: https://doi.org/10.1111/cas.16141-
dc.relation.ispartofCancer Science, 2024, vol. 115, num.5, p. 1505-1519-
dc.relation.urihttps://doi.org/10.1111/cas.16141-
dc.rightscc-by-nc-nd (c) Teixido, Cristina et al., 2024-
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.sourceArticles publicats en revistes (Biomedicina)-
dc.subject.classificationFibrosi pulmonar-
dc.subject.classificationCàncer de pulmó-
dc.subject.classificationFibroblasts-
dc.subject.otherPulmonary fibrosis-
dc.subject.otherLung cancer-
dc.subject.otherFibroblasts-
dc.titleAberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma-
dc.typeinfo:eu-repo/semantics/article-
dc.typeinfo:eu-repo/semantics/publishedVersion-
dc.identifier.idgrec752829-
dc.date.updated2025-01-27T14:05:01Z-
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess-
dc.identifier.pmid38476010-
Appears in Collections:Articles publicats en revistes (Biomedicina)

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