{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T03:43:02Z","timestamp":1791517382732,"version":"4.3.4"},"reference-count":85,"publisher":"American Society for Clinical Investigation","issue":"3","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":62,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"crossref","award":["MOH-000155"],"award-info":[{"award-number":["MOH-000155"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"crossref"}]},{"name":"National Cancer Institute","award":["R01CA42978,P50CA196510,P50CA257911,U01CA199235,P01CA203657,R35CA232113"],"award-info":[{"award-number":["R01CA42978,P50CA196510,P50CA257911,U01CA199235,P01CA203657,R35CA232113"]}]},{"DOI":"10.13039\/100001784","name":"Pancreatic Cancer Action Network","doi-asserted-by":"crossref","award":["22-WG-DERB"],"award-info":[{"award-number":["22-WG-DERB"]}],"id":[{"id":"10.13039\/100001784","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.S. Department of Defense","award":["W81XWH2110692"],"award-info":[{"award-number":["W81XWH2110692"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,2,2]]},"abstract":"<jats:p>\n                    <jats:italic>GATA6<\/jats:italic>\n                    is a master regulator of differentiation in the pancreas, and its expression levels determine the 2 main molecular subtypes of pancreatic cancer. High GATA6 levels contribute to the classical pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why\n                    <jats:italic>GATA6<\/jats:italic>\n                    expression varies across pancreatic cancers and what regulates\n                    <jats:italic>GATA6<\/jats:italic>\n                    expression remain elusive. Here, we report that oncogenic KRAS-activated ERK signaling suppresses\n                    <jats:italic>GATA6<\/jats:italic>\n                    transcription in pancreatic cancers.\n                    <jats:italic>GATA6<\/jats:italic>\n                    mRNA levels inversely correlated with KRAS\/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a\n                    <jats:italic>GATA6<\/jats:italic>\n                    -\n                    <jats:italic>EGFP<\/jats:italic>\n                    reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for\n                    <jats:italic>GATA6<\/jats:italic>\n                    . Active ERK stabilized JUNB protein, while KRAS\/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of\n                    <jats:italic>GATA6<\/jats:italic>\n                    . Upregulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells, and KRAS\/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS\/ERK signaling suppresses\n                    <jats:italic>GATA6<\/jats:italic>\n                    to cause dedifferentiation in pancreatic cancer. Combining KRAS\/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.\n                  <\/jats:p>","DOI":"10.1172\/jci191370","type":"journal-article","created":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T17:00:21Z","timestamp":1764694821000},"source":"Crossref","is-referenced-by-count":3,"title":["Oncogenic KRAS\/ERK\/JUNB signaling suppresses differentiation regulator GATA6 in pancreatic cancer"],"prefix":"10.1172","volume":"136","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1614-7798","authenticated-orcid":true,"given":"Zheng","family":"Zhong","sequence":"first","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinang","family":"Cao","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Ju","family":"Liao","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raman","family":"Sethi","sequence":"additional","affiliation":[{"name":"Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Klomp","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center and"},{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clint A.","family":"Stalnecker","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center and"},{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinmiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."},{"name":"Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), Singapore."},{"name":"Centre for Computational Biology, Duke-NUS Medical School, Singapore."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wan","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Channing J.","family":"Der","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center and"},{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6976-850X","authenticated-orcid":true,"given":"David M.","family":"Virshup","sequence":"additional","affiliation":[{"name":"Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore."},{"name":"Department of Pediatrics, Duke University, Durham, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"issue":"1","key":"B1","first-page":"12","article-title":"Cancer statistics, 2024","volume":"74","author":"Siegel","year":"2024","journal-title":"CA: A Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.10.007"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00840-w"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3398"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-3724"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-24-1164"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.modpat.2023.100102"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1242\/dev.164384"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2012-303328"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2016.12.026"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2017.01.001"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2015-311256"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-321397"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1172\/JCI156305"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03362-3"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00418-1"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0566-9"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0740"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0177"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0908-1"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7859rev"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2018.02.007"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2005482"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001331200"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.517"},{"issue":"3","key":"B26","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1136\/gutjnl-2021-325803","article-title":"GATA4 and GATA6 loss-of-expression is associated with extinction of the classical programme and poor outcome in pancreatic ductal adenocarcinoma","volume":"72","author":"de Andr\u00e9s","year":"2022","journal-title":"Gut"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10500"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-022-02007-7"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk0775"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.ado2402"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nature16965"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-22-2945"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-28480-9"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/s41422-019-0195-y"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3437"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.01.029"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1002\/1873-3468.12740"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(97)80068-3"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.08.023"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcn.2008.09.005"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2014.519"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.235"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.20.7425-7436.2003"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01776-06"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4474"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.12.024"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2016.05.016"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01800-9"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110538"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-308042"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-0035"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.07.024"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.08.001"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2013.12.004"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0245-4"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1172\/JCI59227"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2013.11.052"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0289"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0421"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2008.12.081"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.04.023"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2013.25"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1126\/science.adk0850"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-94544-3"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3047"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.02.002"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk1031"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gku936"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1164-8"},{"key":"B70","doi-asserted-by":"crossref","DOI":"10.12688\/f1000research.3928.2","article-title":"edgeR: a versatile tool for the analysis of shRNA-seq and CRISPR-Cas9 genetic screens","volume":"3","author":"Dai","year":"2014","journal-title":"F1000Res"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.14806\/ej.17.1.200"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq033"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2010.05.004"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbad538"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw257"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.10.6477"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1947"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.10082.1"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-023-01767-y"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/191370\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:45:21Z","timestamp":1779209121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/191370"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,2]]},"references-count":85,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,12,2]]},"published-print":{"date-parts":[[2026,2,2]]}},"alternative-id":["10.1172\/JCI191370"],"URL":"https:\/\/doi.org\/10.1172\/jci191370","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,2]]},"article-number":"e191370"}}