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https://hdl.handle.net/2445/218004
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DC Field | Value | Language |
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dc.contributor.author | Teixido, Cristina | - |
dc.contributor.author | Fernández Nogueira, Patricia | - |
dc.contributor.author | Galbis, José Marcelo | - |
dc.contributor.author | Alcaraz, Jordi | - |
dc.contributor.author | Duch, Paula | - |
dc.contributor.author | Díaz Valdivia, Natalia | - |
dc.contributor.author | Gabasa Ferràndez, Marta | - |
dc.contributor.author | Ikemori, Rafael | - |
dc.contributor.author | Arshakyan, Marselina | - |
dc.contributor.author | Llorente, Alejandro | - |
dc.contributor.author | Ramírez, Josep | - |
dc.contributor.author | Pereda, Javier | - |
dc.contributor.author | Chuliá Peris, Lourdes | - |
dc.contributor.author | Hilberg, Frank | - |
dc.contributor.author | Reguart, Noemí | - |
dc.contributor.author | Radisky, Derek C | - |
dc.contributor.author | Alcaraz, Jordi | - |
dc.date.accessioned | 2025-01-27T14:05:01Z | - |
dc.date.available | 2025-01-27T14:05:01Z | - |
dc.date.issued | 2024-03-12 | - |
dc.identifier.issn | 1347-9032 | - |
dc.identifier.uri | https://hdl.handle.net/2445/218004 | - |
dc.description.abstract | The 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.extent | 15 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Wiley | - |
dc.relation.isformatof | Reproducció del document publicat a: https://doi.org/10.1111/cas.16141 | - |
dc.relation.ispartof | Cancer Science, 2024, vol. 115, num.5, p. 1505-1519 | - |
dc.relation.uri | https://doi.org/10.1111/cas.16141 | - |
dc.rights | cc-by-nc-nd (c) Teixido, Cristina et al., 2024 | - |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.source | Articles publicats en revistes (Biomedicina) | - |
dc.subject.classification | Fibrosi pulmonar | - |
dc.subject.classification | Càncer de pulmó | - |
dc.subject.classification | Fibroblasts | - |
dc.subject.other | Pulmonary fibrosis | - |
dc.subject.other | Lung cancer | - |
dc.subject.other | Fibroblasts | - |
dc.title | Aberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.identifier.idgrec | 752829 | - |
dc.date.updated | 2025-01-27T14:05:01Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 38476010 | - |
Appears in Collections: | Articles publicats en revistes (Biomedicina) |
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873950.pdf | 35.25 MB | Adobe PDF | View/Open |
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