{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T11:46:33Z","timestamp":1784202393249,"version":"3.55.0"},"reference-count":40,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["OCENW.XS21.2.003"],"award-info":[{"award-number":["OCENW.XS21.2.003"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cholangiocarcinoma (CCA) is a rare but devastating liver cancer which is commonly diagnosed at a late stage and often resistant to chemotherapy. Bcl\u20102 family members, which control apoptotic cell death, are known to be involved in the chemoresistance of some cancer types. This study investigated the role of Bcl\u20102 family members in the chemoresistance of cholangiocarcinoma organoids (CCAOs) in both undifferentiated and matured branching phenotypes (BRCCAOs). Patient\u2010derived CCAOs and BRCCAOs were cultured to assess chemoresistance to an FDA\u2010approved anticancer drug panel by testing cell viability using ATP quantification and apoptotic cell death by cleaved caspase 3 staining. More specifically, sensitivity to the first\u2010line drug gemcitabine was tested in combination with Bcl\u20102 family inhibitors or activators. We found that in gemcitabine\u2010resistant CCAOs, inhibition of Bcl\u2010xl could overcome gemcitabine resistance and induce apoptotic cell death. Although inhibition of Mcl\u20101 or activation of Bax induced spontaneous cell death, this could not overcome gemcitabine resistance. The BRCCAOs, which mimic tumor architecture better than CCAOs, show broader chemoresistance to anticancer drugs. Of note, in the resistant BRCCAOs, Bcl\u2010xl inhibition could restore gemcitabine sensitivity. In conclusion, this study shows that targeting Bcl\u2010xl can overcome chemoresistance to gemcitabine in CCA organoids. CCAOs and BRCCAOs provide good preclinical models for testing new drug combinations and assessing personalized therapeutic approaches.<\/jats:p>","DOI":"10.1002\/ijc.35483","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T08:27:43Z","timestamp":1747988863000},"page":"1694-1708","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Apoptosis regulators of the Bcl\u20102 family play a key role in chemoresistance of cholangiocarcinoma organoids"],"prefix":"10.1002","volume":"157","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7199-1506","authenticated-orcid":false,"given":"Wunan","family":"Mi","sequence":"first","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilles S.","family":"van Tienderen","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaojun","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"},{"name":"Department of Organ Transplantation Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Broeders","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Monfils","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henk P.","family":"Roest","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0651-5334","authenticated-orcid":false,"given":"Luc J. W.","family":"van der Laan","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9908-6673","authenticated-orcid":false,"given":"Monique M. A.","family":"Verstegen","sequence":"additional","affiliation":[{"name":"Department of Surgery Erasmus MC Transplant Institute, University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1368-7646(02)00002-X"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-020-0310-z"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrgastro.2016.51"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt540"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.06.005"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1407-6"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-022-01780-7"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19123950"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2021.188569"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/bcr1323"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8637-6"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-023-00629-4"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00407-4"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-07-5836"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3048"},{"key":"e_1_2_11_18_1","first-page":"2628","article-title":"Venetoclax\u2010rituximab with or without bendamustine vs bendamustine\u2010rituximab in relapsed\/refractory follicular lymphoma","volume":"136","author":"Zinzani PL","year":"2020","journal-title":"Blood"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa4642"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0668-z"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-21-0474"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature19830"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4438"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2022.04.011"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2023.102431"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers6031769"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2015.07.003"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acr.2017.11.001"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addbeh.2021.106882"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81683-9"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15392"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2014.525"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2006.08.027"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature03579"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2353"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-04042-7"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-10-1091"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28741-7"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.2634"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1097\/CAD.0000000000000561"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.1021632"}],"container-title":["International Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ijc.35483","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T05:13:37Z","timestamp":1756098817000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ijc.35483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,23]]},"references-count":40,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,10,15]]}},"alternative-id":["10.1002\/ijc.35483"],"URL":"https:\/\/doi.org\/10.1002\/ijc.35483","archive":["Portico"],"relation":{},"ISSN":["0020-7136","1097-0215"],"issn-type":[{"value":"0020-7136","type":"print"},{"value":"1097-0215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,23]]},"assertion":[{"value":"2024-12-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}