{"doi":"10.1111/cas.16141","title":"Aberrant <scp>TIMP</scp>‐1 production in tumor‐associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma","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.","journal":"Cancer Science","year":2024,"id":463770,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.94,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1294132,"name":"Natalia Díaz‐Valdivia","orcid":"0000-0002-8063-2598","position":1,"is_corresponding":false},{"id":656708,"name":"Marta Gabasa","orcid":"0000-0002-3758-2265","position":2,"is_corresponding":false},{"id":656709,"name":"Rafael Ikemori","orcid":"0000-0002-8825-3947","position":3,"is_corresponding":false},{"id":656711,"name":"Marselina Arshakyan","orcid":"0000-0001-8707-6304","position":4,"is_corresponding":false},{"id":1294133,"name":"Patricia Fernández‐Nogueira","orcid":"0000-0002-7246-490X","position":5,"is_corresponding":false},{"id":656715,"name":"Alejandro Llorente","orcid":"0000-0001-6582-130X","position":6,"is_corresponding":false},{"id":1294134,"name":"Cristina Teixidó","orcid":"0000-0002-7226-6567","position":7,"is_corresponding":false},{"id":656718,"name":"José Ramírez","orcid":"0000-0002-7833-1374","position":8,"is_corresponding":false},{"id":1294135,"name":"Javier Pereda","orcid":"0000-0002-8690-8938","position":9,"is_corresponding":false},{"id":373459,"name":"Lourdes Chuliá‐Peris","orcid":"0000-0002-0355-8187","position":10,"is_corresponding":false},{"id":1294136,"name":"José M. Galbis","orcid":"0000-0002-1058-0171","position":11,"is_corresponding":false},{"id":1294137,"name":"Frank Hilberg","orcid":"0000-0001-8925-7336","position":12,"is_corresponding":false},{"id":656719,"name":"Noemı́ Reguart","orcid":"0000-0001-8190-499X","position":13,"is_corresponding":false},{"id":426728,"name":"Derek C. Radisky","orcid":"0000-0002-1962-8784","position":14,"is_corresponding":false},{"id":656721,"name":"Jordi Alcaraz","orcid":"0000-0001-7898-1599","position":15,"is_corresponding":false},{"id":656713,"name":"Paula Duch","orcid":"0000-0002-8326-847X","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:04:33.257852Z","pmid":"38476010","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}