{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:44:43Z","timestamp":1791726283993,"version":"4.3.4"},"reference-count":15,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T00:00:00Z","timestamp":1759190400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2022R1A2C1011889"],"award-info":[{"award-number":["2022R1A2C1011889"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1A5A2031185"],"award-info":[{"award-number":["2020R1A5A2031185"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2020R1C1C1007832"],"award-info":[{"award-number":["2020R1C1C1007832"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["HCRI23011"],"award-info":[{"award-number":["HCRI23011"]}]},{"name":"Chonnam National University Hospital Biomedical Research Institute","award":["HCRI23010"],"award-info":[{"award-number":["HCRI23010"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Brain metastases (BM) from non-small cell lung cancer (NSCLC) represent a significant clinical challenge, characterized by poor prognosis and treatment resistance. While cancer-associated fibroblasts (CAFs) are recognized as crucial components of the BM tumor microenvironment (TME), their mechanistic contributions to disease progression and therapeutic resistance remain poorly understood. In this study, we demonstrated that patient-derived BM-CAFs significantly enhanced NSCLC cell proliferation, migration, invasion and therapeutic resistance in vitro. Mechanistically, BM-CAFs promoted epithelial\u2013mesenchymal transition (EMT) and cancer stem cell (CSC) phenotypes through upregulation of key transcription factors. In-vivo experiments showed that co-injection of NSCLC cells with BM-CAFs accelerated tumor growth and enhanced cisplatin resistance. Molecular analysis revealed these effects were mediated through distinct mechanisms whereby IL26 activated the JAK\u2013STAT3 pathway, while CX3CL1 activated both JAK\u2013STAT3 and AKT\u2013mTOR pathways. Importantly, neutralizing antibodies against IL26 and CX3CL1 effectively suppressed their respective signaling pathways and reversed EMT and CSC characteristics. In summary, our findings establish the IL26 and CX3CL1 signaling as a critical mediator of BM-CAF-induced tumor progression and therapy resistance in NSCLC BM, suggesting a potential therapeutic strategy for this challenging disease.<\/jats:p>","DOI":"10.1186\/s40164-025-00713-9","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T07:40:22Z","timestamp":1759218022000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Brain metastasis-associated cancer fibroblasts drive tumor progression and therapeutic resistance through IL26 and CX3CL1 signaling in non-small-cell lung cancer"],"prefix":"10.1186","volume":"14","author":[{"given":"S. M. Abdus","family":"Salam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eshrat","family":"Jahan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Jung","family":"Ahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Sun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeong Jin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue Jee","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae-Young","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Young","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Jung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roo Ji","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae-Hyuk","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joon Haeng","family":"Rhee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung Keun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Hee","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Hwa","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Sub","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,30]]},"reference":[{"issue":"1","key":"713_CR1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41568-019-0220-y","volume":"20","author":"A Boire","year":"2019","unstructured":"Boire A, Brastianos PK, Garzia L, Valiente M. Brain metastasis. Nat Rev Cancer. 2019;20(1):4\u201311.","journal-title":"Nat Rev Cancer"},{"issue":"4","key":"713_CR2","doi-asserted-by":"crossref","first-page":"e373","DOI":"10.1016\/j.cllc.2018.01.007","volume":"19","author":"SN Waqar","year":"2018","unstructured":"Waqar SN, Samson PP, Robinson CG, Bradley J, Devarakonda S, Du L, et al. Non-small-cell lung cancer with brain metastasis at presentation. Clin Lung Cancer. 2018;19(4):e373\u20139.","journal-title":"Clin Lung Cancer"},{"key":"713_CR3","doi-asserted-by":"crossref","first-page":"1221113","DOI":"10.3389\/fimmu.2023.1221113","volume":"14","author":"EM Brozos-Vazquez","year":"2023","unstructured":"Brozos-Vazquez EM, Rodriguez-Lopez C, Cortegoso-Mosquera A, Lopez-Landrove S, Muinelo-Romay L, Garcia-Gonzalez J, et al. Immunotherapy in patients with brain metastasis: advances and challenges for the treatment and the application of Circulating biomarkers. Front Immunol. 2023;14:1221113.","journal-title":"Front Immunol"},{"issue":"1","key":"713_CR4","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1186\/s12935-022-02599-7","volume":"22","author":"B Feng","year":"2022","unstructured":"Feng B, Wu J, Shen B, Jiang F, Feng J. Cancer-associated fibroblasts and resistance to anticancer therapies: status, mechanisms, and countermeasures. Cancer Cell Int. 2022;22(1):166.","journal-title":"Cancer Cell Int"},{"issue":"1","key":"713_CR5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12943-019-0994-2","volume":"18","author":"ME Fiori","year":"2019","unstructured":"Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. 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Signal Transduct Target Ther. 2021;6(1):218.","journal-title":"Signal Transduct Target Ther"}],"container-title":["Experimental Hematology &amp; Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00713-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s40164-025-00713-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s40164-025-00713-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T20:04:43Z","timestamp":1759262683000},"score":1,"resource":{"primary":{"URL":"https:\/\/ehoonline.biomedcentral.com\/articles\/10.1186\/s40164-025-00713-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,30]]},"references-count":15,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["713"],"URL":"https:\/\/doi.org\/10.1186\/s40164-025-00713-9","relation":{},"ISSN":["2162-3619"],"issn-type":[{"value":"2162-3619","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,30]]},"assertion":[{"value":"12 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Institutional Review Board of Chonnam National University Hwasun Hospital and conducted in accordance with the Declaration of Helsinki (CNUHH-2019-218, CNUHH-2024-114). Written informed consent to use clinical data and surgically resected specimens was obtained from all patients or their legal surrogates. The experimental protocol was approved by the Chonnam National University Medical School Research Institutional Animal Care and Use Committee (CNU IACUC-H-2023-59), and all animal experiments were conducted following recognized principles for animal management and use (DHU publication, NIH 80\u2009\u2212\u200923).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have read and approved the fnal manuscript and consent to publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"120"}}