{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T20:14:02Z","timestamp":1758399242820,"version":"3.44.0"},"reference-count":38,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T00:00:00Z","timestamp":1751846400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP23ck0106802\/JP23ama221119"],"award-info":[{"award-number":["JP23ck0106802\/JP23ama221119"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["JP23H00378"],"award-info":[{"award-number":["JP23H00378"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The tumor immune microenvironment plays a key role in the regulation of cancer progression. Recent studies have suggested a relation between diverse tumor genotypes and tumor immune microenvironment phenotypes for cholangiocarcinoma (CCA). However, the contribution of tumor\u2010infiltrating immune cells to CCA progression has remained unclear, underscoring the need for genetically defined CCA models in immunocompetent mice. We here aimed to generate genetically engineered and transplantable CCA organoids from C57BL\/6 mice and to investigate the role of tumor\u2010infiltrating immune cells in CCA progression with this model. CCA organoids were generated ex\u00a0vivo with the use of the CRISPR\/Cas9 system. Orthotopic transplantation of CCA organoids harboring mutations in <jats:italic>Smad4<\/jats:italic>, <jats:italic>Trp53<\/jats:italic>, and <jats:italic>Kras<\/jats:italic> into wild\u2010type C57BL\/6 mice resulted in tumor formation accompanied by distant metastasis. Selective depletion of immune cell types in the tumor\u2010bearing mice revealed an antitumor action of tumor\u2010infiltrating neutrophils (TINs) that was mediated by direct killing of cancer cells through the production of reactive oxygen species. Furthermore, administration of recombinant human granulocyte colony\u2010stimulating factor (rhG\u2010CSF) increased the number and cytotoxicity of TINs, suppressed tumor growth, and prolonged the survival of tumor\u2010bearing mice. Finally, combination treatment with rhG\u2010CSF and standard chemotherapy resulted in a synergistic attenuation of tumor growth. Our study therefore provides a syngeneic and genetically defined mouse model of CCA and highlights the therapeutic potential of targeting TINs with rhG\u2010CSF.<\/jats:p>","DOI":"10.1111\/cas.70129","type":"journal-article","created":{"date-parts":[[2025,7,7]],"date-time":"2025-07-07T09:56:44Z","timestamp":1751882204000},"page":"2457-2470","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antitumor Activity of Tumor\u2010Infiltrating Neutrophils Revealed by a Syngeneic Mouse Model of Cholangiocarcinoma"],"prefix":"10.1111","volume":"116","author":[{"given":"Osamu","family":"Sugahara","sequence":"first","affiliation":[{"name":"Anticancer Strategies Laboratory Advanced Research Initiative, Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeru","family":"Oka","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeaki","family":"Sugiyama","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reona","family":"Wada","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsunaki","family":"Higa","sequence":"additional","affiliation":[{"name":"Anticancer Strategies Laboratory Advanced Research Initiative, Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7185-1529","authenticated-orcid":false,"given":"Keiichi I.","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Anticancer Strategies Laboratory Advanced Research Initiative, Institute of Science Tokyo  Tokyo Japan"},{"name":"Department of Molecular and Cellular Biology Medical Institute of Bioregulation, Kyushu University  Fukuoka Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,7,7]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575\u2010020\u20100310\u2010z"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.08.021"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.401"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201018\u20100078"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jjco\/hyaa088"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31862"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.11.030"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.02.008"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.050358"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5994"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.02.045"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568\u2010020\u20100281\u2010y"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010019\u20100141\u20108"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010021\u201000571\u20106"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgt397"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216260"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jitc\u20102020\u2010001946"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43586\u2010022\u201000174\u2010y"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3802"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.12.009"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580\u2010020\u20100259\u20103"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.4.1427"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2297"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaq1067"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379\u2010020\u201000656\u2010y"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2023.05.010"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.02.016"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.771210"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201016596\u20109"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010022\u201005400\u2010x"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010019\u20100054\u2010z"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.08.012"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384101.2014.950163"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.6.1737.1737"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80504-X"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aax0249"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy311"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70129","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T10:30:38Z","timestamp":1756722638000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70129"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,7]]},"references-count":38,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1111\/cas.70129"],"URL":"https:\/\/doi.org\/10.1111\/cas.70129","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"type":"print","value":"1347-9032"},{"type":"electronic","value":"1349-7006"}],"subject":[],"published":{"date-parts":[[2025,7,7]]},"assertion":[{"value":"2025-02-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-07","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}