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Recurrence often occurs with metastasis, for which cancer cells must adapt to isolation stress to successfully colonize distant organs. While the fibronectin\u2013integrin axis has been implicated in this adaptation, its regulatory mechanisms require further elaboration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We utilized genetically engineered PDAC mouse models with c-Rel knockout, overexpression and fibronectin (FN1) depletion, alongside in vitro assays, to assess EMP, extracellular matrix (ECM) remodeling, and resistance to anchorage-independent growth. Functional analyses, including transcriptomics, Cut&amp;Run, flow cytometry, immunohistochemistry, and metastatic assays, were performed to elucidate the role of c-Rel in fibronectin\u2013integrin signaling during PDAC progression.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified c-Rel as an oncogenic driver in PDAC that promotes EMP, ECM remodeling, and survival under isolation stress. c-Rel directly regulates FN1 and CD61\/integrin \u03b23 (ITGB3) transcription, enhancing cellular adaptability in metastatic settings. While FN1 is dispensable for EMT, its absence significantly impairs metastatic colonization and anchorage-independent growth.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that c-Rel can regulate PDAC progression and metastasis by modulating the tumor microenvironment and stress resistance. Targeting the c-Rel\u2013fibronectin\u2013integrin axis may offer novel therapeutic strategies to mitigate disease progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12943-025-02486-5","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T11:27:28Z","timestamp":1765798048000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["c-Rel drives pancreatic cancer metastasis through fibronectin-integrin signaling-induced isolation stress resistance and EMT"],"prefix":"10.1186","volume":"25","author":[{"given":"D.","family":"Bak\u0131rd\u00f6\u011fen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K.","family":"G\u00f6rg\u00fcl\u00fc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Xin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S.","family":"Alcal\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Ruiz-Ca\u00f1as","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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Cited 2024 July 11.","DOI":"10.1038\/s41598-019-41695-z"}],"container-title":["Molecular Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12943-025-02486-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12943-025-02486-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12943-025-02486-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T16:30:25Z","timestamp":1781627425000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12943-025-02486-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":101,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["2486"],"URL":"https:\/\/doi.org\/10.1186\/s12943-025-02486-5","relation":{},"ISSN":["1476-4598"],"issn-type":[{"value":"1476-4598","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"assertion":[{"value":"10 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 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 doesn\u2019t include human participants. For the human data and tissues, the fundamental ethical principles promoted by the European Union have been strictly respected, as described in the Charter of Fundamental Rights of the EU (2000\/C364\/01). The project was evaluated by the Ethical Committee of University Hospital Clinico San Carlos (B.0000725; PT17\/0015\/0040; ISCIII-FEDER). The institutional review board (IRB) of University Hospital Clinico San Carlos evaluated the present study and approved it on March 10, 2017, with approval number n\u00b0 17\/091-E. All patients provided written informed consent for the use of their biological samples for research purposes. Moreover, the criteria of the Declaration of Helsinki (last revision 2013) and the Spanish Biomedical Research Law (14\/2007, of July 3) were met. Ethical principles were followed regarding the use of human samples and the generation of databases while respecting the Spanish Organic Law on Data Protection (LO 15\/1999) and the European Union Fundamental Rights of the EU (2000\/C364\/01). The confidentiality of all personal, clinicopathological, and\/or genetic data of patients will always be maintained per current legislation (2016\/679 of the European Parliament and of the Council of April 27th, 2016 on Data Protection, Personal Data Protection Law 3\/2018, of December 5th, on the Personal Data Protection that guarantees all digital rights, and the provisions in this regard contemplated in Law 41\/2002, of November 14th). The Government of Upper Bavaria (Regierung von Oberbayern) reviewed and approved all animal housing and experimental procedures, following the Federal German Guidelines for Ethical Treatment of Animals (ROB-55.2-2532.Vet_02-20-134, ROB-55.2-2532.Vet_02-20-97, ROB-55.2-2532.Vet_03-21-68).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","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":"16"}}