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DCCs from epithelial cancers are mostly detected by antibodies directed against histogenetic markers such as cytokeratin or EpCAM. It has been argued that marker\u2010negative metastatic founder cells might escape detection. We therefore used ex vivo sphere formation for functional detection of candidate metastasis founders. We generated cell suspensions from 199 LN samples of 131 lung cancer patients and placed them into non\u2010adherent cell culture. Sphere formation was associated with detection of DCCs using EpCAM immunocytology and with significantly poorer prognosis. The prognostic impact of sphere formation was strongly associated with high numbers of EpCAM\u2010positive DCCs and aberrant genotypes of expanded spheres. We also noted sphere formation in patients with no evidence of lymphatic spread, however such spheres showed infrequent expression of signature genes associated with spheres from EpCAM\u2010positive samples and displayed neither typical lung cancer mutations (<jats:italic>KRAS<\/jats:italic>, <jats:italic>TP53<\/jats:italic>, <jats:italic>ERBB1<\/jats:italic>) nor copy number variations, but might be linked to disease progression &gt;5\u2009years post curative surgery. We conclude that EpCAM identifies relevant disease\u2010driving DCCs, that such cells can be expanded for model generation and that further research is needed to clarify the functional and prognostic role of rare EpCAM\u2010negative sphere forming cells.<\/jats:p>","DOI":"10.1002\/ijc.34658","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T12:54:05Z","timestamp":1691585645000},"page":"1854-1867","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ex vivo expansion of lung cancer\u2010derived disseminated cancer cells from lymph nodes identifies cells associated with metastatic progression"],"prefix":"10.1002","volume":"153","author":[{"given":"Steffi","family":"Treitschke","sequence":"first","affiliation":[{"name":"Fraunhofer Institute for Toxicology and Experimental Medicine, Division of Personalized Tumor Therapy  Regensburg 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