{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T19:22:10Z","timestamp":1789154530252,"version":"build-2803163510"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82404358, 82273084"],"award-info":[{"award-number":["82404358, 82273084"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Gastric cancer (GC) develops through a sequence from chronic gastritis to intestinal metaplasia (IM) and carcinoma, with Helicobacter pylori (HP) as a key driver; however, the molecular mediators linking inflammation to malignant transformation remain unclear. We integrated single-cell RNA sequencing and spatial transcriptomics of gastric mucosal samples from atrophic gastritis, IM, and GC, including HP positive (+) and HP negative (-) cases, to map cellular heterogeneity, differentiation trajectories, and pathway activities. Our analyses revealed that IM epithelium represents a transitional state between normal and malignant epithelial lineages, characterized by enhanced WNT signaling that promotes neoplastic progression, whereas H. pylori\u2013associated inflammation activates NF-\u03baB signaling. Across analysis, UPP1 was consistently upregulated in malignant and H. pylori\u2013positive epithelium, increasing along pseudotime toward cancer-like states. Spatial mapping and organoid experiments confirmed that UPP1-high cells had higher intestinal differentiation scores, while UPP1 knockout promoted IM-like morphology in WNT-depleted cultures. Clinically, UPP1 was elevated in GC versus normal tissues, correlated with advanced TNM stage, predicted poor survival, and was higher in HP\n                    <jats:sup>+<\/jats:sup>\n                    tissues. Knockdown in GC cell lines reduced clonogenicity and migration. Collectively, these findings identify UPP1 as a key regulator of epithelial reprogramming and IM, linking H. pylori\u2013driven inflammation with WNT-mediated differentiation, and highlight its potential as a prognostic biomarker and therapeutic target in GC.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1712830","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T07:29:24Z","timestamp":1770622164000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Integrated single-cell and spatial transcriptomics reveal the differentiation drivers of gastric epithelial lineage progression"],"prefix":"10.3389","volume":"17","author":[{"given":"Xuyu","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siying","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianlei","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjun","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Fu","sequence":"additional","affiliation":[{"name":"Dalian Medical University","place":["Dalian, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Yukun","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northern Jiangsu People\u2019s Hospital","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuoqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaoyao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanbing","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The Affiliated Hospital of Yangzhou University, Yangzhou University","place":["Yangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10","DOI":"10.3322\/caac.21871","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1038\/nrc.2017.68","article-title":"Metaplasia: tissue injury adaptation and a precursor to the dysplasia-cancer sequence","volume":"17","author":"Giroux","year":"2017","journal-title":"Nat Rev Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.07.006","article-title":"Gastric intestinal metaplasia revisited: function and regulation of CDX2","volume":"18","author":"Barros","year":"2012","journal-title":"Trends Mol Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.08.028","article-title":"Gastric intestinal metaplasia: real culprit or innocent bystander as a precancerous condition for gastric cancer","volume":"165","author":"Sugano","year":"2023","journal-title":"Gastroenterology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.10.004","article-title":"Spatiotemporal genomic profiling of intestinal metaplasia reveals clonal dynamics of gastric cancer progression","volume":"41","author":"Huang","year":"2023","journal-title":"Cancer Cell"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2019-319826","article-title":"Gastric microbes associated with gastric inflammation, atrophy and intestinal metaplasia 1 year after Helicobacter pylori eradication","volume":"69","author":"Sung","year":"2020","journal-title":"Gut"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1080\/19490976.2020.1762520","article-title":"The role of gastric microbiota in gastric cancer","volume":"11","author":"Stewart","year":"2020","journal-title":"Gut Microbes"},{"key":"B8","doi-asserted-by":"publisher","first-page":"215764","DOI":"10.1016\/j.canlet.2022.215764","article-title":"Helicobacter pylori infection induces stem cell-like properties in Correa cascade of gastric cancer","volume":"542","author":"He","year":"2022","journal-title":"Cancer Lett"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2024.04.016","article-title":"Metabolic regulator ERR\u03b3 governs gastric stem cell differentiation into acid-secreting parietal cells","volume":"31","author":"Adkins-Threats","year":"2024","journal-title":"Cell Stem Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2022.06.021","article-title":"Dysplastic stem cell plasticity functions as a driving force for neoplastic transformation of precancerous gastric mucosa","volume":"163","author":"Min","year":"2022","journal-title":"Gastroenterology"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.10.047","article-title":"Wnt signaling shapes the histologic variation in diffuse gastric cancer","volume":"160","author":"Togasaki","year":"2021","journal-title":"Gastroenterology"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.027","article-title":"Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis","volume":"174","author":"Nanki","year":"2018","journal-title":"Cell"},{"key":"B13","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1038\/s41587-023-01767-y","article-title":"Dictionary learning for integrative, multimodal and scalable single-cell analysis","volume":"42","author":"Hao","year":"2024","journal-title":"Nat Biotechnol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4314","article-title":"Dimensionality reduction for visualizing single-cell data using UMAP","volume":"37","author":"Becht","year":"2018","journal-title":"Nat Biotechnol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-040320-103615","article-title":"The wnt pathway: from signaling mechanisms to synthetic modulators","volume":"91","author":"Rim","year":"2022","journal-title":"Annu Rev Biochem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1109","article-title":"A CRISPR\/cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and nonessential modes of oncogenic transformation","volume":"11","author":"Lo","year":"2021","journal-title":"Cancer Discov"},{"key":"B17","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1136\/gutjnl-2022-328408","article-title":"NNMT enriches for AQP5+ cancer stem cells to drive Malignant progression in early gastric cardia adenocarcinoma","volume":"73","author":"Wang","year":"2023","journal-title":"Gut"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2019.07.008","article-title":"Defining the identity and dynamics of adult gastric isthmus stem cells","volume":"25","author":"Han","year":"2019","journal-title":"Cell Stem Cell"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2022.01.046","article-title":"Helicobacter pylori-induced RASAL2 Through Activation of Nuclear Factor-\u03baB Promotes Gastric Tumorigenesis via \u03b2-catenin Signaling Axis","volume":"162","author":"Cao","year":"2022","journal-title":"Gastroenterology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1186\/s12935-024-03598-6","article-title":"Intestinal metaplasia key molecules and UPP1 activation via Helicobacter pylori\/NF-kB: drivers of Malignant progression in gastric cancer","volume":"24","author":"Chen","year":"2024","journal-title":"Cancer Cell Int"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-333029","article-title":"The road to a world-unified approach to the management of patients with gastric intestinal metaplasia: a review of current guidelines","volume":"73","author":"Dinis-Ribeiro","year":"2024","journal-title":"Gut"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-329492","article-title":"Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation","volume":"73","author":"Takeuchi","year":"2024","journal-title":"Gut"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1136\/gut.52.1.1","article-title":"Is intestinal metaplasia of the stomach reversible","volume":"52","author":"Walker","year":"2003","journal-title":"Gut"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-322368","article-title":"Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus","volume":"69","author":"Liou","year":"2020","journal-title":"Gut"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-1523","article-title":"Expansion of gastric intestinal metaplasia with copy number aberrations contributes to field cancerization","volume":"82","author":"Kumagai","year":"2022","journal-title":"Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"280","DOI":"10.3322\/caac.21559","article-title":"Epithelial ovarian cancer: Evolution of management in the era of precision medicine","volume":"69","author":"Lheureux","year":"2019","journal-title":"CA Cancer J Clin"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(25)00052-2","article-title":"Gastric cancer","volume":"405","author":"Sundar","year":"2025","journal-title":"Lancet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2023.02.044","article-title":"A liquid biopsy signature for the early detection of gastric cancer in patients","volume":"165","author":"Guo","year":"2023","journal-title":"Gastroenterology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2024-332705","article-title":"Where are we with gastric cancer screening in Europe in 2024","volume":"73","author":"Leja","year":"2024","journal-title":"Gut"},{"key":"B30","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.semcancer.2023.04.009","article-title":"Application of artificial intelligence for improving early detection and prediction of therapeutic outcomes for gastric cancer in the era of precision oncology","volume":"93","author":"Wang","year":"2023","journal-title":"Semin Cancer Biol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06073-w","article-title":"Uridine-derived ribose fuels glucose-restricted pancreatic cancer","volume":"618","author":"Nwosu","year":"2023","journal-title":"Nature"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-023-00774-2","article-title":"Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions","volume":"5","author":"Skinner","year":"2023","journal-title":"Nat Metab"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.01.013","article-title":"Nucleosides are overlooked fuels in central carbon metabolism","volume":"35","author":"Strefeler","year":"2024","journal-title":"Trends Endocrinol Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.83774","article-title":"UPP1 enhances bladder cancer progression and gemcitabine resistance through AKT","volume":"20","author":"Du","year":"2024","journal-title":"Int J Biol Sci"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1712830\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T09:59:55Z","timestamp":1771927195000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1712830\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,9]]},"references-count":34,"alternative-id":["10.3389\/fimmu.2026.1712830"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1712830","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,9]]},"article-number":"1712830"}}