{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:23:56Z","timestamp":1787822636229,"version":"build-2784847793"},"reference-count":22,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82203045"],"award-info":[{"award-number":["82203045"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013058","name":"Jiangsu Provincial Key Research and Development Program","doi-asserted-by":"publisher","award":["BE2021745"],"award-info":[{"award-number":["BE2021745"]}],"id":[{"id":"10.13039\/501100013058","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007452","name":"Wu Jieping Medical Foundation","doi-asserted-by":"publisher","award":["320.6750.2024\u201024\u20107"],"award-info":[{"award-number":["320.6750.2024\u201024\u20107"]}],"id":[{"id":"10.13039\/100007452","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,8,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, with therapeutic efficacy hindered by tumor heterogeneity and drug resistance. While organoid technology offers unprecedented opportunities to model tumor complexity, systematic platforms for chemo\u2010targeted combination screening and molecular mechanisms underlying chemoresistance remain underexplored in Chinese populations. Here, we established a biobank of 17 patient\u2010derived CRC organoids (85% success rate) from treatment\u2010na\u00efve surgical specimens, preserving histopathological fidelity and molecular diversity of parental tumors. High\u2010throughput drug screening across eight clinical regimens revealed different responses. To dissect chemoresistance mechanisms, six organoids representing extreme phenotypes (three sensitive and three resistant, based on IC50 difference for irinotecan\u2009+\u2009raltitrexed) were selected from this cohort for single\u2010cell transcriptomic analysis. Single\u2010cell transcriptomics of irinotecan\u2009+\u2009raltitrexed\u2010treated organoids identified chemoresistance\u2010associated clonal expansion of epithelial subpopulations (cluster_0), characterized by overexpression of REG4\/TFF1\/TFF3 and epithelial keratins (KRT19\/KRT8\/KRT18). Intercellular network analysis revealed intra\u2010epithelial communication as a resistance hub, mediated by 32 ligand\u2010receptor pairs. Integration with TCGA\u2010COAD cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009378) demonstrated intratumoral heterogeneity (ITH) score as an independent prognostic determinant, outperforming stemness\/angiogenesis metrics. Machine learning consensus identified CEACAM6 and KRT19 as dual regulators of mortality and ITH through epithelial plasticity networks. Our multi\u2010omics framework establishes organoid\u2010guided chemoresistance mechanisms while proposing ITH quantification targeting as precision strategies. This study bridges critical gaps in CRC therapeutic personalization, offering clinically actionable insights for overcoming treatment failure.\n                  <\/jats:p>","DOI":"10.1096\/fj.202600610r","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T14:37:33Z","timestamp":1787236653000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Patient\u2010Derived Organoid and Single\u2010Cell Multiomics Reveal Evolution Driven by\n                    <scp>CEACAM6<\/scp>\n                    \/\n                    <scp>KRT19<\/scp>\n                    \u2010Mediated Heterogeneity"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5503-9426","authenticated-orcid":false,"given":"Changwen","family":"Jing","sequence":"first","affiliation":[{"name":"Molecular Pathology Laboratory, Jiangsu Cancer Hospital &amp; Jiangsu Institute of Cancer Research &amp; the Affiliated Cancer Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Wang","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, Jiangsu Cancer Hospital &amp; Jiangsu Institute of Cancer Research &amp; the Affiliated Cancer Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Cao","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, Jiangsu Cancer Hospital &amp; Jiangsu Institute of Cancer Research &amp; the Affiliated Cancer Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Science and Technology Department, Jiangsu Cancer Hospital Jiangsu Institute of Cancer Research &amp; the Affiliated Cancer Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchun","family":"Huang","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, Jiangsu Cancer Hospital &amp; Jiangsu Institute of Cancer Research &amp; the Affiliated Cancer Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuetong","family":"Yu","sequence":"additional","affiliation":[{"name":"College of Public Health, Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingzhe","family":"Li","sequence":"additional","affiliation":[{"name":"Yangzhou University Medical College  Yangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Ma","sequence":"additional","affiliation":[{"name":"Molecular Pathology Laboratory, Jiangsu Cancer Hospital &amp; Jiangsu Institute of Cancer Research &amp; the Affiliated Cancer Hospital of Nanjing Medical University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3348\/kjr.2024.0575"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2022.02.002"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3727\/97818823455816X14786040691928"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2017.166"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0007-6"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dead085"},{"issue":"31","key":"e_1_2_11_10_1","article-title":"Patient\u2010Derived Organoids From Colorectal Cancer With Paired Liver Metastasis Reveal Tumor Heterogeneity and Predict Response to Chemotherapy","volume":"9","author":"Mo S.","year":"2022","journal-title":"Advancement of Science"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-3980"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2022.100911"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2022.10.001"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112324"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41585-020-00400-w"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00139.2021"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-019-0020-z"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01233-9"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/cpr.13249"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2024.5615"},{"issue":"2","key":"e_1_2_11_21_1","first-page":"195","article-title":"THADA Inhibits Autophagy and Increases 5\u2010FU Sensitivity in Gastric Cancer Cells via the PI3K\/AKT\/mTOR Signaling Pathway","volume":"27","author":"Lin X.","year":"2024","journal-title":"Iranian Journal of Basic Medical Sciences"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000875"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S419235"}],"container-title":["The FASEB 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