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In this study, we employed single\u2010nucleus multi\u2010omics analysis, including single\u2010nucleus RNA\u2010seq and single\u2010nucleus ATAC\u2010seq, on over 100,000 high\u2010quality nuclei to investigate the molecular landscape of both primary tissue and patient\u2010derived organoids (PDOs). Our analysis showed that normal PDOs (N\u2010PDOs) derived from tissue adjacent to tumors replicate the cellular composition and differentiation trajectory of colorectal crypts. In contrast, tumor PDOs (T\u2010PDOs) showed patient\u2010specific transcriptomic and epigenomic heterogeneity yet consistently maintained a stem cell\u2010like state. T\u2010PDOs retained the somatic mutation profile of the primary tumor while also exhibiting de novo mutations not detected in either the primary tumor or N\u2010PDOs. Notably, inferred cell\u2013cell interaction analysis highlighted the activin signaling pathway as a potential unique feature of fibroblast\u2010epithelial interactions within the tumor microenvironment. This study provides a comprehensive view of the transition from normal to malignant colorectal epithelium and underscores the utility of PDOs as a faithful model for capturing both conserved and patient\u2010specific features of colorectal cancer.<\/jats:p>","DOI":"10.1002\/ijc.70103","type":"journal-article","created":{"date-parts":[[2025,8,23]],"date-time":"2025-08-23T09:36:02Z","timestamp":1755941762000},"page":"2619-2634","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Single\u2010cell multi\u2010omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying\n                    <scp>CRC<\/scp>\n                    \u2010unique features"],"prefix":"10.1002","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1706-118X","authenticated-orcid":false,"given":"Zhijun","family":"Yu","sequence":"first","affiliation":[{"name":"Princess Maxima Center for Pediatric Oncology  Utrecht The Netherlands"},{"name":"Department of Precision Medicine University of Campania \u201cLuigi Vanvitelli\u201d  Naples Italy"},{"name":"Department of Molecular Biology, Faculty of Science Radboud Institute for Molecular Life Sciences, Radboud University  Nijmegen The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merel","family":"Derksen","sequence":"additional","affiliation":[{"name":"HUB Organoids B.V., Utrecht, the Netherlands, part of the Life Science Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigit M.","family":"te Pas","sequence":"additional","affiliation":[{"name":"Princess Maxima Center for Pediatric Oncology  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5773-5436","authenticated-orcid":false,"given":"Sabrina","family":"Ladst\u00e4tter","sequence":"additional","affiliation":[{"name":"CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4043-0959","authenticated-orcid":false,"given":"Rene","family":"Overmeer","sequence":"additional","affiliation":[{"name":"HUB Organoids B.V., Utrecht, the Netherlands, part of the Life Science Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0215-1692","authenticated-orcid":false,"given":"Peter","family":"Brazda","sequence":"additional","affiliation":[{"name":"Princess Maxima Center for Pediatric Oncology  Utrecht The Netherlands"},{"name":"Center for Translational Immunology University Medical Center Utrecht, Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8195-9939","authenticated-orcid":false,"given":"Marc","family":"van de Wetering","sequence":"additional","affiliation":[{"name":"Princess Maxima Center for Pediatric Oncology  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farzin","family":"Pourfarzad","sequence":"additional","affiliation":[{"name":"HUB Organoids B.V., Utrecht, the Netherlands, part of the Life Science Business of Merck KGaA  Darmstadt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert G. 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