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The epithelial-to-mesenchymal transition (EMT) of CTCs is considered a critical step in tumour metastasis; however, it may confound traditional epithelial feature-based CTC isolation and detection. We applied single-cell copy number alteration (CNA) analysis for the identification of genomic alterations to confirm the neoplastic nature of circulating cells with only mesenchymal phenotypes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We isolated CTCs from blood samples collected from 46 NSCLC patients using the Parsortix system. Enriched cells were subjected to immunofluorescent staining for CTC identification using a multi-marker panel comprising both epithelial and mesenchymal markers. A subset of isolated CTCs was subjected to whole genome amplification (WGA) and low-pass whole-genome sequencing (LP-WGS) for the analysis of copy number alterations (CNAs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CTCs were detected in 16\/46 (34.8%) patients, inclusive of CK<jats:sup>+<\/jats:sup>\/EpCAM<jats:sup>+<\/jats:sup>CTCs (3\/46, 6.5%) and Vim<jats:sup>+<\/jats:sup>CTCs (13\/46, 28.3%). Clusters of Vim<jats:sup>+<\/jats:sup>cells were detected in 8 samples, which constitutes 50% of the total number of NSCLC patients with CTCs. No patients had detectable hybrid CK<jats:sup>+<\/jats:sup>\/EpCAM<jats:sup>+<\/jats:sup>\/Vim<jats:sup>+<\/jats:sup>cells. All of the tested CK<jats:sup>+<\/jats:sup>\/EpCAM<jats:sup>+<\/jats:sup>CTCs and 7\/8 Vim<jats:sup>+<\/jats:sup>CTCs or CTC clusters carried CNAs confirming their neoplastic nature. Notably, the Vim<jats:sup>+<\/jats:sup>cluster with no CNAs was characterised by spindle morphology and, therefore, defined as normal mesenchymal circulating cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our results revealed that CK-negative, vimentin-expressing cells represent a large proportion of CTCs detected in NSCLC patients, which are likely missed by standard epithelial-marker-dependent CTC categorisation.<\/jats:p><\/jats:sec>","DOI":"10.1007\/s00432-022-04202-y","type":"journal-article","created":{"date-parts":[[2022,7,28]],"date-time":"2022-07-28T03:34:42Z","timestamp":1658979282000},"page":"1941-1950","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Powering single-cell genomics to unravel circulating tumour cell subpopulations in non-small cell lung cancer patients"],"prefix":"10.1007","volume":"149","author":[{"given":"Emmanuel","family":"Acheampong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Morici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afaf","family":"Abed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Bowyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Du-Bois","family":"Asante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weitao","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Millward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8613-3570","authenticated-orcid":false,"given":"Elin S.","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron B.","family":"Beasley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,28]]},"reference":[{"key":"4202_CR1","doi-asserted-by":"publisher","first-page":"2393","DOI":"10.3390\/cells9112393","volume":"9","author":"E Acheampong","year":"2020","unstructured":"Acheampong E, Abed A, Morici M, Bowyer S, Amanuel B, Lin W, Millward M, Gray ES (2020) Tumour PD-L1 expression in small-cell lung cancer: a systematic review and meta-analysis. 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