{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:59:31Z","timestamp":1787018371427,"version":"build-2736575974"},"reference-count":63,"publisher":"American Society for Clinical Investigation","issue":"14","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":64,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health (NIH) and National Cancer Institute (NCI) grants","award":["R01CA228216,DP2CA174499,P50CA217694,U54CA224079,P50CA092629,P50CA221745,R01CA193837,U01CA224044,R01CA208100"],"award-info":[{"award-number":["R01CA228216,DP2CA174499,P50CA217694,U54CA224079,P50CA092629,P50CA221745,R01CA193837,U01CA224044,R01CA208100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,15]]},"abstract":"<jats:p>\n                    Based on the observation that loss-of-function mutations of\n                    <jats:italic>KMT2C<\/jats:italic>\n                    and\n                    <jats:italic>KMT2D<\/jats:italic>\n                    (\n                    <jats:italic>KMT2C\/D<\/jats:italic>\n                    ) are enriched and co-occur in gastric adenocarcinoma, we developed genetically engineered mouse models (GEMMs) to conditionally knock out\n                    <jats:italic>Kmt2c<\/jats:italic>\n                    and\n                    <jats:italic>Kmt2d<\/jats:italic>\n                    in gastric epithelial cells. We observed that\n                    <jats:italic>Kmt2c\/d<\/jats:italic>\n                    loss led to nuclear dysplasia, cellular crowding, and expansion of cells with mixed gastric lineage markers. When combined with\n                    <jats:italic>Pten<\/jats:italic>\n                    deletion,\n                    <jats:italic>Kmt2c\/d<\/jats:italic>\n                    loss drove rapid development of muscle-invasive gastric adenocarcinoma as early as 3 weeks after Cre-mediated gene deletion. The adenocarcinoma exhibited decreased expression of gastric lineage markers and increased expression of intestinal differentiation markers, phenocopying human intestinal-type gastric adenocarcinoma. Bioinformatic integration of single-cell RNA-seq of our GEMMs and human gastric cancer datasets showed coclustering of normal and of cancerous gastric epithelial cells.\n                    <jats:italic>Kmt2c\/d<\/jats:italic>\n                    knockout in gastric epithelium reduced protein synthesis but upregulated transcription of ribosomal proteins, rendering the cells hypersensitive to mTOR complex 1 (mTORC1) inhibitors. Additionally,\n                    <jats:italic>Kmt2c\/d<\/jats:italic>\n                    knockout increased MHC class I molecule expression and enhanced antigen presentation. Combination of mTORC1 inhibition and anti\u2013programmed cell death 1 immunotherapy markedly suppressed tumor growth in immune-competent mice. Together, these findings reveal the role of\n                    <jats:italic>Kmt2c<\/jats:italic>\n                    \/\n                    <jats:italic>d<\/jats:italic>\n                    loss in gastric cancer initiation and suggest potential therapeutic strategies for\n                    <jats:italic>KMT2C\/D<\/jats:italic>\n                    -deficient gastric cancer.\n                  <\/jats:p>","DOI":"10.1172\/jci194462","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:00:48Z","timestamp":1778601648000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss of Kmt2c\/d promotes gastric cancer and confers vulnerability to mTORC1 and PD-1 inhibition"],"prefix":"10.1172","volume":"136","author":[{"given":"Naitao","family":"Wang","sequence":"first","affiliation":[{"name":"Shenzhen University Medical School, Shenzhen, China."},{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8777-4580","authenticated-orcid":true,"given":"Dan","family":"Li","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohini R.","family":"Pachai","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana M.","family":"Schoeps","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudi","family":"Bao","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Peking University People\u2019s Hospital, Beijing, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo Hyun","family":"Cho","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makhzuna N.","family":"Khudoynazarova","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kae","family":"Kristoff","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion","family":"Liu","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Department of Surgery,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pathology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yelena Y.","family":"Janjigian","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0159-5531","authenticated-orcid":true,"given":"Ping","family":"Chi","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0171-3884","authenticated-orcid":true,"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA."},{"name":"Department of Medicine, Weill Cornell Medical College, New York, New York, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"issue":"3","key":"B1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31288-5"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature13480"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3850"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/apm.1965.64.1.31"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1109"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-322660"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad9780"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-020-0278-0"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-02015-y"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01181-13"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.005"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00361-6"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.11.015"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01446-3"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3943"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-021-01840-3"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1021\/jm401002r"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01930-8"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nature12113"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2764"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3544"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00686-w"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0161084"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0642-1"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.09.026"},{"issue":"3","key":"B28","first-page":"390","article-title":"Dissection of gastric homeostasis in vivo facilitates permanent capture of isthmus-like stem cells in vitro","volume":"25","author":"Huebner","year":"2023","journal-title":"Nat Cell Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2016.11.001"},{"key":"B30","doi-asserted-by":"crossref","DOI":"10.1093\/database\/baz046","article-title":"PanglaoDB: a web server for exploration of mouse and human single-cell RNA sequencing data","volume":"2019","author":"Franzen","year":"2019","journal-title":"Database (Oxford)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108819"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2010.08.003"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-024-00874-2"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/ajg.2009.728"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.07.006"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.04.052"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-0683"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-019-0619-0"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-1448"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/nature10912"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1172\/JCI160025"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111482"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.4149\/neo_2013_025"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15180"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-0824"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.10.004"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-1523"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00620-7"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02465-7"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1177\/17588359231205853"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14041054"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.48.3552"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0252"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf1329"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adc9446"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1382-0"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41695-z"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.1923"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2008-9-9-r137"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw257"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06575-7"}],"container-title":["Journal of Clinical Investigation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.jci.org\/articles\/view\/194462\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T18:02:28Z","timestamp":1784052148000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jci.org\/articles\/view\/194462"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":63,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,6,2]]},"published-print":{"date-parts":[[2026,7,15]]}},"alternative-id":["10.1172\/JCI194462"],"URL":"https:\/\/doi.org\/10.1172\/jci194462","relation":{},"ISSN":["1558-8238"],"issn-type":[{"value":"1558-8238","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]},"article-number":"e194462"}}