{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T06:17:44Z","timestamp":1793081864504,"version":"4.5.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T00:00:00Z","timestamp":1748822400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Genet"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Circulating tumor cell (CTC) clusters are highly efficient metastatic seeds in various cancers. Yet, their genetic heterogeneity and clonal architecture is poorly characterized. Using whole-exome sequencing coupled with phylogenetic inference from CTC clusters of patients with breast and prostate cancer, as well as mouse cancer models alongside barcode-mediated clonal tracking in vivo, we demonstrate oligoclonal composition of individual CTC clusters. These results improve our understanding of metastasis-relevant clonal dynamics.<\/jats:p>","DOI":"10.1038\/s41588-025-02205-2","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T05:03:22Z","timestamp":1748840602000},"page":"1357-1361","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Phylogenetic inference reveals clonal heterogeneity in circulating tumor cell clusters"],"prefix":"10.1038","volume":"57","author":[{"given":"David","family":"Gremmelspacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8559-1212","authenticated-orcid":false,"given":"Johannes","family":"Gawron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara M.","family":"Szczerba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Jahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6111-0754","authenticated-orcid":false,"given":"Francesc","family":"Castro-Giner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5357-2705","authenticated-orcid":false,"given":"Jack","family":"Kuipers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Singer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8993-7320","authenticated-orcid":false,"given":"Francesco","family":"Marass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6013-0355","authenticated-orcid":false,"given":"Ana","family":"Gvozdenovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selina","family":"Budinjas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heike","family":"Pueschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8085-6006","authenticated-orcid":false,"given":"Cyrill A.","family":"Rentsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred","family":"Zippelius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viola","family":"Heinzelmann-Schwarz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kurzeder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter Paul","family":"Weber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Rochlitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Vetter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0573-6119","authenticated-orcid":false,"given":"Niko","family":"Beerenwinkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9579-6918","authenticated-orcid":false,"given":"Nicola","family":"Aceto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"2205_CR1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16295-5","volume":"11","author":"X Hua","year":"2020","unstructured":"Hua, X. et al. Genetic and epigenetic intratumor heterogeneity impacts prognosis of lung adenocarcinoma. Nat. Commun. 11, 2459 (2020).","journal-title":"Nat. Commun."},{"key":"2205_CR2","doi-asserted-by":"publisher","first-page":"10051","DOI":"10.18632\/oncotarget.7067","volume":"7","author":"LGT Morris","year":"2016","unstructured":"Morris, L. G. T. et al. Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival. Oncotarget 7, 10051\u201310063 (2016).","journal-title":"Oncotarget"},{"key":"2205_CR3","doi-asserted-by":"publisher","first-page":"2109","DOI":"10.1056\/NEJMoa1616288","volume":"376","author":"M Jamal-Hanjani","year":"2017","unstructured":"Jamal-Hanjani, M. et al. Tracking the evolution of non\u2013small-cell lung cancer. N. Engl. J. Med. 376, 2109\u20132121 (2017).","journal-title":"N. Engl. J. Med."},{"key":"2205_CR4","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/s41559-021-01615-9","volume":"6","author":"R Noble","year":"2021","unstructured":"Noble, R. et al. Spatial structure governs the mode of tumour evolution. Nat. Ecol. Evol. 6, 207\u2013217 (2021).","journal-title":"Nat. Ecol. Evol."},{"key":"2205_CR5","first-page":"889","volume":"36","author":"LA Llofta","year":"1976","unstructured":"Llofta, L. A., Klelnerman, J. & Saldel, G. M. The significance of hematogenous tumor cell clumps in the metastatic process. Cancer Res. 36, 889\u2013894 (1976).","journal-title":"Cancer Res."},{"key":"2205_CR6","doi-asserted-by":"publisher","first-page":"016001","DOI":"10.1088\/1478-3975\/9\/1\/016001","volume":"9","author":"EH Cho","year":"2012","unstructured":"Cho, E. H. et al. Characterization of circulating tumor cell aggregates identified in patients with epithelial tumors. Phys. Biol. 9, 016001 (2012).","journal-title":"Phys. Biol."},{"key":"2205_CR7","first-page":"4080","volume":"7","author":"B Molnar","year":"2001","unstructured":"Molnar, B. et al. Circulating tumor cell clusters in the peripheral blood of colorectal cancer patients. Cancer Res. 7, 4080\u20134085 (2001).","journal-title":"Cancer Res."},{"key":"2205_CR8","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1016\/j.cell.2014.07.013","volume":"158","author":"N Aceto","year":"2014","unstructured":"Aceto, N. et al. Circulating tumor cell clusters are oligoclonal precursors of breast cancer metastasis. Cell 158, 1110\u20131122 (2014).","journal-title":"Cell"},{"key":"2205_CR9","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/nature14347","volume":"520","author":"G Gundem","year":"2015","unstructured":"Gundem, G. et al. The evolutionary history of lethal metastatic prostate cancer. Nature 520, 353\u2013357 (2015).","journal-title":"Nature"},{"key":"2205_CR10","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1093\/annonc\/mdx278","volume":"28","author":"Q Wei","year":"2017","unstructured":"Wei, Q. et al. Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis. Ann. Oncol. 28, 2135\u20132141 (2017).","journal-title":"Ann. Oncol."},{"key":"2205_CR11","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1038\/s41588-020-0628-z","volume":"52","author":"Z Hu","year":"2020","unstructured":"Hu, Z., Li, Z., Ma, Z. & Curtis, C. Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases. Nat. Genet. 52, 701\u2013708 (2020).","journal-title":"Nat. Genet."},{"key":"2205_CR12","doi-asserted-by":"publisher","first-page":"10995","DOI":"10.1073\/pnas.1508074112","volume":"112","author":"JZ Sanborn","year":"2015","unstructured":"Sanborn, J. Z. et al. Phylogenetic analyses of melanoma reveal complex patterns of metastatic dissemination. Proc. Natl Acad. Sci. USA 112, 10995\u201311000 (2015).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2205_CR13","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/s41586-019-0915-y","volume":"566","author":"BM Szczerba","year":"2019","unstructured":"Szczerba, B. M. et al. Neutrophils escort circulating tumour cells to enable cell cycle progression. Nature 566, 553\u2013557 (2019).","journal-title":"Nature"},{"key":"2205_CR14","doi-asserted-by":"publisher","first-page":"5194","DOI":"10.1158\/0008-5472.CAN-16-2072","volume":"77","author":"V Murlidhar","year":"2017","unstructured":"Murlidhar, V. et al. Poor prognosis indicated by venous circulating tumor cell clusters in early-stage lung cancers. Cancer Res. 77, 5194\u20135206 (2017).","journal-title":"Cancer Res."},{"key":"2205_CR15","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s10549-016-4026-2","volume":"161","author":"C Wang","year":"2017","unstructured":"Wang, C. et al. Longitudinally collected CTCs and CTC-clusters and clinical outcomes of metastatic breast cancer. Breast Cancer Res. Treat. 161, 83\u201394 (2017).","journal-title":"Breast Cancer Res. Treat."},{"key":"2205_CR16","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1200\/JCO.2010.33.3716","volume":"30","author":"J-M Hou","year":"2012","unstructured":"Hou, J.-M. et al. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J. Clin. Oncol. 30, 525\u2013532 (2012).","journal-title":"J. Clin. Oncol."},{"key":"2205_CR17","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1038\/s41591-024-03486-6","volume":"31","author":"C Kurzeder","year":"2025","unstructured":"Kurzeder, C. et al. Digoxin for reduction of circulating tumor cell cluster size in metastatic breast cancer: a proof-of-concept trial. Nat. Med. 31, 1120\u20131124 (2025).","journal-title":"Nat. Med."},{"key":"2205_CR18","doi-asserted-by":"publisher","first-page":"E854","DOI":"10.1073\/pnas.1508541113","volume":"113","author":"KJ Cheung","year":"2016","unstructured":"Cheung, K. J. et al. Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc. Natl Acad. Sci. USA 113, E854\u2013E863 (2016).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2205_CR19","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-016-0936-x","volume":"17","author":"K Jahn","year":"2016","unstructured":"Jahn, K., Kuipers, J. & Beerenwinkel, N. Tree inference for single-cell data. Genome Biol. 17, 86 (2016).","journal-title":"Genome Biol."},{"key":"2205_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-07627-7","volume":"9","author":"J Singer","year":"2018","unstructured":"Singer, J., Kuipers, J., Jahn, K. & Beerenwinkel, N. Single-cell mutation identification via phylogenetic inference. Nat. Commun. 9, 5144 (2018).","journal-title":"Nat. Commun."},{"key":"2205_CR21","doi-asserted-by":"publisher","first-page":"2155","DOI":"10.1158\/0008-5472.CAN-22-2717","volume":"83","author":"N Roda","year":"2023","unstructured":"Roda, N. et al. A rare subset of primary tumor cells with concomitant hyper-activation of extracellular matrix remodeling and dsRNA-IFN1 signaling metastasizes in breast cancer. Cancer Res. 83, 2155\u20132170 (2023).","journal-title":"Cancer Res."},{"key":"2205_CR22","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34041-x","volume":"13","author":"LA Baldwin","year":"2022","unstructured":"Baldwin, L. A. et al. DNA barcoding reveals ongoing immunoediting of clonal cancer populations during metastatic progression and immunotherapy response. Nat. Commun. 13, 6539 (2022).","journal-title":"Nat. Commun."},{"key":"2205_CR23","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1038\/s41591-019-0593-1","volume":"25","author":"F Chemi","year":"2019","unstructured":"Chemi, F. et al. Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse. Nat. Med. 25, 1534\u20131539 (2019).","journal-title":"Nat. Med."},{"key":"2205_CR24","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/s41586-022-04875-y","volume":"607","author":"Z Diamantopoulou","year":"2022","unstructured":"Diamantopoulou, Z. et al. The metastatic spread of breast cancer accelerates during sleep. Nature 607, 156\u2013162 (2022).","journal-title":"Nature"},{"key":"2205_CR25","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1002\/cyto.b.20560","volume":"80B","author":"RL Eifler","year":"2011","unstructured":"Eifler, R. L. et al. Enrichment of circulating tumor cells from a large blood volume using leukapheresis and elutriation: proof of concept. Cytometry B Clin. Cytom. 80B, 100\u2013111 (2011).","journal-title":"Cytometry B Clin. Cytom."},{"key":"2205_CR26","doi-asserted-by":"publisher","first-page":"108105","DOI":"10.1016\/j.celrep.2020.108105","volume":"32","author":"C Donato","year":"2020","unstructured":"Donato, C. et al. Hypoxia triggers the intravasation of clustered circulating tumor cells. Cell Rep. 32, 108105 (2020).","journal-title":"Cell Rep."},{"key":"2205_CR27","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1016\/j.cell.2018.11.046","volume":"176","author":"S Gkountela","year":"2019","unstructured":"Gkountela, S. et al. Circulating tumor cell clustering shapes DNA methylation to enable metastasis seeding. Cell 176, 98\u2013112.e14 (2019).","journal-title":"Cell"},{"key":"2205_CR28","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1126\/science.1253533","volume":"345","author":"M Yu","year":"2014","unstructured":"Yu, M. et al. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility. Science 345, 216\u2013220 (2014).","journal-title":"Science"},{"key":"2205_CR29","doi-asserted-by":"publisher","first-page":"2081","DOI":"10.1038\/nprot.2016.138","volume":"11","author":"IC Macaulay","year":"2016","unstructured":"Macaulay, I. C. et al. Separation and parallel sequencing of the genomes and transcriptomes of single cells using G&T-seq. Nat. Protoc. 11, 2081\u20132103 (2016).","journal-title":"Nat. Protoc."},{"key":"2205_CR30","doi-asserted-by":"publisher","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows\u2013Wheeler transform. Bioinformatics 25, 1754\u20131760 (2009).","journal-title":"Bioinformatics"},{"key":"2205_CR31","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. et al. The sequence alignment\/map format and SAMtools. Bioinformatics 25, 2078\u20132079 (2009).","journal-title":"Bioinformatics"},{"key":"2205_CR32","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.12688\/f1000research.10082.1","volume":"5","author":"MJ Ahdesm\u00e4ki","year":"2016","unstructured":"Ahdesm\u00e4ki, M. J., Gray, S. R., Johnson, J. H. & Lai, Z. Disambiguate: an open-source application for disambiguating two species in next generation sequencing data from grafted samples. F1000Res. 5, 2741 (2016).","journal-title":"F1000Res."},{"key":"2205_CR33","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","volume":"43","author":"MA DePristo","year":"2011","unstructured":"DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491\u2013498 (2011).","journal-title":"Nat. Genet."},{"key":"2205_CR34","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1093\/bioinformatics\/btv566","volume":"32","author":"K Okonechnikov","year":"2016","unstructured":"Okonechnikov, K., Conesa, A. & Garc\u00eda-Alcalde, F. Qualimap 2: advanced multi-sample quality control for high-throughput sequencing data. Bioinformatics 32, 292\u2013294 (2016).","journal-title":"Bioinformatics"},{"key":"2205_CR35","doi-asserted-by":"publisher","first-page":"3047","DOI":"10.1093\/bioinformatics\/btw354","volume":"32","author":"P Ewels","year":"2016","unstructured":"Ewels, P., Magnusson, M., Lundin, S. & K\u00e4ller, M. MultiQC: summarize analysis results for multiple tools and samples in a single report. Bioinformatics 32, 3047\u20133048 (2016).","journal-title":"Bioinformatics"},{"key":"2205_CR36","doi-asserted-by":"crossref","unstructured":"Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly 6, 80\u201392 (2012).","DOI":"10.4161\/fly.19695"},{"key":"2205_CR37","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-018-0531-8","volume":"10","author":"D Tamborero","year":"2018","unstructured":"Tamborero, D. et al. Cancer Genome Interpreter annotates the biological and clinical relevance of tumor alterations. Genome Med. 10, 25 (2018).","journal-title":"Genome Med."},{"key":"2205_CR38","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/nprot.2014.006","volume":"9","author":"S Picelli","year":"2014","unstructured":"Picelli, S. et al. Full-length RNA-seq from single cells using Smart-seq2. Nat. Protoc. 9, 171\u2013181 (2014).","journal-title":"Nat. Protoc."},{"key":"2205_CR39","doi-asserted-by":"publisher","unstructured":"Gawron, J. cbg-ethz\/CTC-SCITE: distribute on multiple architectures (v1.0.2). Zenodo https:\/\/doi.org\/10.5281\/zenodo.14922630 (2025).","DOI":"10.5281\/zenodo.14922630"}],"container-title":["Nature Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41588-025-02205-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41588-025-02205-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41588-025-02205-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,13]],"date-time":"2025-06-13T12:24:02Z","timestamp":1749817442000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41588-025-02205-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":39,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["2205"],"URL":"https:\/\/doi.org\/10.1038\/s41588-025-02205-2","relation":{},"ISSN":["1061-4036","1546-1718"],"issn-type":[{"value":"1061-4036","type":"print"},{"value":"1546-1718","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6]]},"assertion":[{"value":"9 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 June 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"N.A. is a cofounder and member of the board of PAGE Therapeutics AG, listed as an inventor in patent applications related to CTCs, a paid consultant for companies with an interest in liquid biopsies and a Novartis shareholder. C.R. is a cofounder, employee and member of the board of PAGE Therapeutics AG. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}