{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T03:29:38Z","timestamp":1789097378477,"version":"build-2803163510"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["1046092"],"award-info":[{"award-number":["1046092"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Clin Exp Metastasis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Differentiation grade of colorectal cancers (CRC) is histologically defined by the proportion of the tumour which retains the glandular architecture of the normal colon. Poorly differentiated CRCs display loss of glandular architecture and canonical markers of colonic differentiation and are associated with increased metastatic capacity and poorer prognosis. It is currently unclear whether poorly differentiated cells within a heterogeneous primary tumour are more likely to establish metastases and if this cellular trait is conserved in the secondary tumours, or whether metastasis is largely stochastic, with most cells in the primary tumour harboring metastatic potential. To explore this, we examined the concordance in histological grade, expression of markers of colonic differentiation, and epithelial to mesenchymal transition (EMT) in 67 matched primary and metastatic CRCs. Tumour differentiation grade was scored categorically, and expression of differentiation and EMT markers were scored as continuous variables. In matched primary-metastatic pairs, tumour grade was concordant in 88% of cases (59\/67 pairs), irrespective of the site of metastasis. In tumour pairs with discordant grade (n\u2009=\u20098), tumour grade was higher in the metastatic lesion in 6\/8 (75%) cases. Consistent with the histological concordance, expression of the key driver of colonic differentiation (CDX2); colonic lineage-specific markers (VIL1, MUC2, SYN and CHG); and the markers of epithelial-to-mesenchymal transition (E-Cadherin and Vimentin) were highly concordant between matched primary and metastatic lesions. Finally, no staining of the squamous lineage marker Cytokeratin5\/6 was observed in either primary or metastatic tumours. Tumour grade assessed histologically or using expression of markers of colonic differentiation or epithelial to mesenchymal transition was largely concordant between primary and metastatic CRC. These findings complement previously reported genomic similarities between primary and metastatic lesions and demonstrate that the histological grade of a primary tumour can in most cases inform the differentiation grade of associated metastatic lesions.<\/jats:p>","DOI":"10.1007\/s10585-025-10380-z","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T05:56:40Z","timestamp":1760680600000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Differentiation grade is highly concordant between matched primary and metastatic colorectal cancer"],"prefix":"10.1007","volume":"42","author":[{"given":"Camilla M.","family":"Reehorst","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer K.","family":"Mooi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles J.","family":"Uy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen A.","family":"Needham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Ellis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian Y.","family":"Luk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Jenkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Nightingale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Chionh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Behren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niall C.","family":"Tebbutt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David S.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Mariadason","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"10380_CR1","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/S0140-6736(84)92636-9","volume":"2","author":"LS Freedman","year":"1984","unstructured":"Freedman LS, Macaskill P, Smith AN (1984) Multivariate analysis of prognostic factors for operable rectal cancer. Lancet 2:733\u2013736","journal-title":"Lancet"},{"key":"10380_CR2","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.jss.2014.10.005","volume":"194","author":"LJ Garcia-Florez","year":"2014","unstructured":"Garcia-Florez LJ, Gomez-Alvarez G, Frunza AM et al (2014) Predictive markers of response to neoadjuvant therapy in rectal cancer. J Surg Res 194:120\u2013126","journal-title":"J Surg Res"},{"key":"10380_CR3","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1097\/PAS.0b013e318235edee","volume":"36","author":"H Ueno","year":"2012","unstructured":"Ueno H, Kajiwara Y, Shimazaki H et al (2012) New criteria for histologic grading of colorectal cancer. Am J Surg Pathol 36:193\u2013201","journal-title":"Am J Surg Pathol"},{"key":"10380_CR4","unstructured":"Digestive System Tumours (2019) WHO Classification of Tumours, Fifth Edition, Volume 1"},{"key":"10380_CR5","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1093\/annonc\/mdx052","volume":"28","author":"R Dienstmann","year":"2017","unstructured":"Dienstmann R, Mason MJ, Sinicrope FA et al (2017) Prediction of overall survival in stage II and III colon cancer beyond TNM system: a retrospective, pooled biomarker study. Ann Oncol 28:1023\u20131031","journal-title":"Ann Oncol"},{"key":"10380_CR6","doi-asserted-by":"publisher","first-page":"3277","DOI":"10.1002\/cncr.30181","volume":"122","author":"L Casadaban","year":"2016","unstructured":"Casadaban L, Rauscher G, Aklilu M et al (2016) Adjuvant chemotherapy is associated with improved survival in patients with stage II colon cancer. Cancer 122:3277\u20133287","journal-title":"Cancer"},{"key":"10380_CR7","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1007\/s00384-019-03279-1","volume":"34","author":"A Romiti","year":"2019","unstructured":"Romiti A, Roberto M, Marchetti P et al (2019) Study of histopathologic parameters to define the prognosis of stage II colon cancer. Int J Colorectal Dis 34:905\u2013913","journal-title":"Int J Colorectal Dis"},{"key":"10380_CR8","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1097\/PAS.0b013e31829ab1c1","volume":"37","author":"JH Kim","year":"2013","unstructured":"Kim JH, Rhee YY, Bae JM et al (2013) Loss of CDX2\/CK20 expression is associated with poorly differentiated carcinoma, the CpG island methylator phenotype, and adverse prognosis in microsatellite-unstable colorectal cancer. Am J Surg Pathol 37:1532\u20131541","journal-title":"Am J Surg Pathol"},{"key":"10380_CR9","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1016\/j.ajpath.2012.01.006","volume":"180","author":"D Arango","year":"2012","unstructured":"Arango D, Al-Obaidi S, Williams DS et al (2012) Villin expression is frequently lost in poorly differentiated colon cancer. Am J Pathol 180:1509\u20131521","journal-title":"Am J Pathol"},{"key":"10380_CR10","first-page":"347","volume":"27","author":"L Harbaum","year":"2012","unstructured":"Harbaum L, Pollheimer MJ, Kornprat P et al (2012) Keratin 20 - a diagnostic and prognostic marker in colorectal cancer? Histol Histopathol 27:347\u2013356","journal-title":"Histol Histopathol"},{"key":"10380_CR11","doi-asserted-by":"publisher","first-page":"1564","DOI":"10.1016\/j.cell.2023.03.003","volume":"186","author":"S Gerstberger","year":"2023","unstructured":"Gerstberger S, Jiang Q, Ganesh K (2023) Metastasis. Cell 186:1564\u20131579","journal-title":"Cell"},{"key":"10380_CR12","doi-asserted-by":"publisher","first-page":"4283","DOI":"10.1073\/pnas.0712345105","volume":"105","author":"S Jones","year":"2008","unstructured":"Jones S, Chen WD, Parmigiani G et al (2008) Comparative lesion sequencing provides insights into tumor evolution. Proc Natl Acad Sci USA 105:4283\u20134288","journal-title":"Proc Natl Acad Sci U S A"},{"key":"10380_CR13","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1186\/s13059-015-0589-1","volume":"16","author":"IB Tan","year":"2015","unstructured":"Tan IB, Malik S, Ramnarayanan K et al (2015) High-depth sequencing of over 750 genes supports linear progression of primary tumors and metastases in most patients with liver-limited metastatic colorectal cancer. Genome Biol 16:32","journal-title":"Genome Biol"},{"key":"10380_CR14","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1186\/s13059-014-0454-7","volume":"15","author":"AR Brannon","year":"2014","unstructured":"Brannon AR, Vakiani E, Sylvester BE et al (2014) Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions. Genome Biol 15:454","journal-title":"Genome Biol"},{"key":"10380_CR15","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1038\/s41588-019-0423-x","volume":"51","author":"Z Hu","year":"2019","unstructured":"Hu Z, Ding J, Ma Z et al (2019) Quantitative evidence for early metastatic seeding in colorectal cancer. Nat Genet 51:1113\u20131122","journal-title":"Nat Genet"},{"key":"10380_CR16","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1038\/s41575-024-00934-z","volume":"21","author":"A Canellas-Socias","year":"2024","unstructured":"Canellas-Socias A, Sancho E, Batlle E (2024) Mechanisms of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 21:609\u2013625","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"10380_CR17","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1126\/science.aao3791","volume":"362","author":"S Bian","year":"2018","unstructured":"Bian S, Hou Y, Zhou X et al (2018) Single-cell multiomics sequencing and analyses of human colorectal cancer. Science 362:1060\u20131063","journal-title":"Science"},{"key":"10380_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10585-009-9295-2","volume":"27","author":"GAP Ganepola","year":"2010","unstructured":"Ganepola GAP, Mazziotta RM, Weeresinghe D et al (2010) Gene expression profiling of primary and metastatic colon cancers identifies a reduced proliferative rate in metastatic tumors. Clin Exp Metastasis 27:1\u20139","journal-title":"Clin Exp Metastasis"},{"key":"10380_CR19","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1038\/s41586-024-08150-0","volume":"637","author":"A Moorman","year":"2025","unstructured":"Moorman A, Benitez EK, Cambulli F et al (2025) Progressive plasticity during colorectal cancer metastasis. Nature 637:947\u2013954","journal-title":"Nature"},{"key":"10380_CR20","doi-asserted-by":"publisher","first-page":"3191","DOI":"10.1200\/JCO.2009.27.7723","volume":"28","author":"NC Tebbutt","year":"2010","unstructured":"Tebbutt NC, Wilson K, Gebski VJ et al (2010) Capecitabine, bevacizumab, and mitomycin in first-line treatment of metastatic colorectal cancer: results of the Australasian Gastrointestinal Trials Group randomized phase III MAX study. J Clin Oncol 28:3191\u20133198","journal-title":"J Clin Oncol"},{"key":"10380_CR21","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/bjc.2015.209","volume":"113","author":"AJ Weickhardt","year":"2015","unstructured":"Weickhardt AJ, Williams DS, Lee CK et al (2015) Vascular endothelial growth factor D expression is a potential biomarker of bevacizumab benefit in colorectal cancer. Br J Cancer 113:37\u201345","journal-title":"Br J Cancer"},{"key":"10380_CR22","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1111\/his.13975","volume":"76","author":"ID Nagtegaal","year":"2020","unstructured":"Nagtegaal ID, Odze RD, Klimstra D et al (2020) The 2019 WHO classification of tumours of the digestive system. Histopathology 76:182\u2013188","journal-title":"Histopathology"},{"key":"10380_CR23","first-page":"153","volume":"3","author":"M Fleming","year":"2012","unstructured":"Fleming M, Ravula S, Tatishchev SF et al (2012) Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol 3:153\u2013173","journal-title":"J Gastrointest Oncol"},{"key":"10380_CR24","doi-asserted-by":"publisher","first-page":"2239","DOI":"10.1016\/S0002-9440(10)63074-X","volume":"159","author":"T Hinoi","year":"2001","unstructured":"Hinoi T, Tani M, Lucas PC et al (2001) Loss of CDX2 expression and microsatellite instability are prominent features of large cell minimally differentiated carcinomas of the colon. Am J Pathol 159:2239\u20132248","journal-title":"Am J Pathol"},{"key":"10380_CR25","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1136\/gut.51.2.184","volume":"51","author":"D Qualtrough","year":"2002","unstructured":"Qualtrough D, Hinoi T, Fearon E et al (2002) Expression of CDX2 in normal and neoplastic human colon tissue and during differentiation of an in vitro model system. Gut 51:184\u2013190","journal-title":"Gut"},{"key":"10380_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2025.100881","author":"S Ogden","year":"2025","unstructured":"Ogden S, Metic N, Leylek O et al (2025) Phenotypic heterogeneity and plasticity in colorectal cancer metastasis. Cell Genom. https:\/\/doi.org\/10.1016\/j.xgen.2025.100881","journal-title":"Cell Genom"},{"key":"10380_CR27","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/s41388-024-03200-3","volume":"44","author":"T Bording","year":"2025","unstructured":"Bording T, Janik T, Bischoff P et al (2025) GPA33 expression in colorectal cancer can be induced by WNT inhibition and targeted by cellular therapy. Oncogene 44:30\u201341","journal-title":"Oncogene"},{"key":"10380_CR28","doi-asserted-by":"publisher","first-page":"875","DOI":"10.1038\/s42003-025-08251-0","volume":"8","author":"IY Luk","year":"2025","unstructured":"Luk IY, Mooi JK, Mouradov D et al (2025) Model systems and unique biological features of high and low-grade colorectal cancer (CRC) revealed by xenografting 84 human CRC cell lines. Commun Biol 8:875","journal-title":"Commun Biol"},{"key":"10380_CR29","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1186\/s12943-017-0691-y","volume":"16","author":"KCG Berg","year":"2017","unstructured":"Berg KCG, Eide PW, Eilertsen IA et al (2017) Multi-omics of 34 colorectal cancer cell lines - a resource for biomedical studies. Mol Cancer 16:116","journal-title":"Mol Cancer"},{"key":"10380_CR30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0090607","volume":"9","author":"D Chen","year":"2014","unstructured":"Chen D, Huang JF, Liu K et al (2014) BRAFV600E mutation and its association with clinicopathological features of colorectal cancer: a systematic review and meta-analysis. PLoS One 9:e90607","journal-title":"PLoS ONE"},{"issue":"10","key":"10380_CR31","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1016\/j.annonc.2020.06.022","volume":"31","author":"G Argiles","year":"2020","unstructured":"Argiles G, Tabernero J, Labianca R et al (2020) Localised colon cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 31(10):1291\u20131305","journal-title":"Ann Oncol"},{"key":"10380_CR32","doi-asserted-by":"publisher","first-page":"2183","DOI":"10.1158\/2159-8290.CD-24-0421","volume":"14","author":"HA Araujo","year":"2024","unstructured":"Araujo HA, Pechuan-Jorge X, Zhou T et al (2024) Mechanisms of response and tolerance to active RAS inhibition in KRAS-mutant non-small cell lung cancer. Cancer Discov 14:2183\u20132208","journal-title":"Cancer Discov"},{"key":"10380_CR33","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1038\/s41588-020-0633-2","volume":"52","author":"JG Reiter","year":"2020","unstructured":"Reiter JG, Hung WT, Lee IH et al (2020) Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases. Nat Genet 52:692\u2013700","journal-title":"Nat Genet"},{"key":"10380_CR34","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1126\/science.aai8515","volume":"357","author":"K Naxerova","year":"2017","unstructured":"Naxerova K, Reiter JG, Brachtel E et al (2017) Origins of lymphatic and distant metastases in human colorectal cancer. Science 357:55\u201360","journal-title":"Science"}],"container-title":["Clinical &amp; Experimental Metastasis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10585-025-10380-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10585-025-10380-z\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10585-025-10380-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T04:21:45Z","timestamp":1764562905000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10585-025-10380-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,17]]},"references-count":34,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["10380"],"URL":"https:\/\/doi.org\/10.1007\/s10585-025-10380-z","relation":{},"ISSN":["1573-7276"],"issn-type":[{"value":"1573-7276","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,17]]},"assertion":[{"value":"5 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 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":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}}],"article-number":"61"}}