{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:47:27Z","timestamp":1790642847465,"version":"4.1.0"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Higher Education Innovation Fund Project of Gansu Provincial Department of Education","award":["2024B-020"],"award-info":[{"award-number":["2024B-020"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>The inflammation\u2013intestinal metaplasia (IM)\u2013carcinoma cascade has been proposed as a framework for gastric cancer (GC) development, yet the cell-level heterogeneity and microenvironmental remodeling underlying this progression remain poorly characterized. Here, we constructed a single-cell transcriptomic atlas by integrating scRNA-seq data from chronic gastritis (superficial, CGS), IM, cancer-adjacent, and tumor tissues through a unified analytical pipeline. Seven major cell lineages were resolved. Relative to CGS, IM and GC tissues exhibited a progressive contraction of epithelial compartments accompanied by expansion of immune and stromal populations. Copy number variation (CNV) inference identified two tumor-restricted malignant epithelial subgroups\u2014one biased toward differentiation and the other enriched for inflammatory and epithelial\u2013mesenchymal transition (EMT) signatures\u2014as well as putative proto-malignant intermediates that coexisted with phenotypically normal epithelium. Cell\u2013cell communication analysis indicated broadly augmented crosstalk between epithelial cells and T cells, myeloid cells, and fibroblasts, with prominent involvement of a CD44\u2013extracellular matrix (ECM) axis. Pseudotime trajectory analysis placed malignant epithelium at late positions along gastric and pyloric mucosal cell differentiation backbones, coinciding with increasing CNV burden and enrichment of stem-like transcriptional programs. Gene regulatory network analysis revealed coordinated activity of lineage-specification modules (HNF4\/CDX, NR1H4\/ESRRA), proliferative regulons (MYC\/TFDP1), and inflammatory\/EMT-associated programs (FOSL1\/REL\/NF-\u03baB). In independent cohorts, elevated expression of several malignant-epithelium-associated transcription factors\u2014including HNF4A, KLF3, FOSL1, TCF7L2, BCL3, RELB, ONECUT2, and MAF\u2014correlated with unfavorable overall survival. Collectively, these findings provide single-cell-resolution evidence consistent with the proposed three-stage model of gastric carcinogenesis and highlight candidate transcriptional regulators warranting further investigation as potential early-detection biomarkers.<\/jats:p>","DOI":"10.1371\/journal.pone.0347679","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T17:37:27Z","timestamp":1776879447000},"page":"e0347679","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Single-cell atlas of gastric cancer reveals malignant epithelial evolution and regulatory reprogramming of the tumor microenvironment"],"prefix":"10.1371","volume":"21","author":[{"given":"Xiulan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2180-2343","authenticated-orcid":true,"given":"Yunhan","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"issue":"1","key":"pone.0347679.ref001","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1751-2980.2011.00550.x","article-title":"The gastric precancerous cascade","volume":"13","author":"P Correa","year":"2012","journal-title":"J Dig 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