{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T03:50:20Z","timestamp":1792122620128,"version":"4.4.0"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.12375349"],"award-info":[{"award-number":["No.12375349"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.12175167"],"award-info":[{"award-number":["No.12175167"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["No.32400555"],"award-info":[{"award-number":["No.32400555"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018806","name":"Department of Science and Technology of Hubei Province","doi-asserted-by":"publisher","award":["No. 2022EHB035"],"award-info":[{"award-number":["No. 2022EHB035"]}],"id":[{"id":"10.13039\/501100018806","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hubei Talent Program","award":["No. 1180011"],"award-info":[{"award-number":["No. 1180011"]}]}],"content-domain":{"domain":["www.plosmedicine.org"],"crossmark-restriction":false},"short-container-title":["PLoS Med"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Microvascular invasion (MVI) is closely related to the recurrence and metastasis of hepatocellular carcinoma (HCC), but the underlying cellular mechanism remains largely elusive. This study aims to elucidate the regional cellular discrepancy between MVI-positive (MVI\n                      <jats:sup>+<\/jats:sup>\n                      ) and MVI-negative (MVI\n                      <jats:sup>\u2212<\/jats:sup>\n                      ) HCC by integrating Spatial transcriptomics (ST) and spatial metabolomics (SM).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods and findings<\/jats:title>\n                    <jats:p>\n                      ST and SM were performed on six tissue samples from four patients (including 2 MVI\n                      <jats:sup>+<\/jats:sup>\n                      , 2 MVI\n                      <jats:sup>\u2212<\/jats:sup>\n                      , and 2 paratumor tissues), with the integration of 79 public single-cell RNA sequencing datasets of HCC. Patient identity was used as a covariate in the linear equation for regional differentially expressed gene analysis with the ST data. Clinical validation was conducted through multiplex immunofluorescence staining in 79 patients, together with external validation in the cancer genome atlas (TCGA)-liver hepatocellular carcinoma (LIHC) cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u2009299) and an independent microarray dataset (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200962). For cell-type-specific metabolic profiling, spatial transcriptomic-metabolic registration was performed. The functional roles of key metabolites were further validated in vitro using inflammatory cancer-associated fibroblasts (iCAFs) derived from hepatic stellate cells (HSCs) and primary CAFs through co-culture models and various functional assays assessing cell proliferation, migration, and invasion. In the tumor lesion, a malignant\n                      <jats:italic>STMN1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>HMGN2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>GPC3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+<\/jats:italic>\n                      <\/jats:sup>\n                      cell subtype enriched in MVI\n                      <jats:sup>+<\/jats:sup>\n                      HCC was identified, which exhibited enhanced proliferative activity and was associated with poor prognosis. This finding was further confirmed in a local cohort of 79 patients, where multiplex immunofluorescence staining for the three genes (\n                      <jats:italic>STMN1<\/jats:italic>\n                      ,\n                      <jats:italic>HMGN2<\/jats:italic>\n                      , and\n                      <jats:italic>GPC3<\/jats:italic>\n                      ) showed significantly higher expression in the MVI\n                      <jats:sup>+<\/jats:sup>\n                      group than in the MVI\n                      <jats:sup>\u2212<\/jats:sup>\n                      group (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.046). Integrated SM analysis further revealed that this cell population underwent metabolic reprogramming characterized by suppressed glycerolipid metabolism. In the tumor capsule, iCAFs-related genes were downregulated in MVI\n                      <jats:sup>+<\/jats:sup>\n                      cases, and iCAFs were located distally from the tumor boundary. Spatial metabolite mapping showed a strong correlation between taurine and iCAFs, and functional assays demonstrated that taurine promotes HCC proliferation and migration by suppressing iCAF activity. One limitation of this study is the small sample size of spatial omics data, which hinders a more complete molecular functional analysis of the\n                      <jats:italic>STMN1<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>HMGN2<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+<\/jats:italic>\n                      <\/jats:sup>\n                      <jats:italic>GPC3<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>+<\/jats:italic>\n                      <\/jats:sup>\n                      cell subtype and iCAFs in MVI\n                      <jats:sup>+<\/jats:sup>\n                      HCC. Larger-scale ST cohorts are required to further validate and expand the findings of this study.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This integrative spatial atlas proposes a hypothesis that there exists a highly proliferative and metabolically reprogrammed malignant cell subtype in the tumor lesion of MVI\n                      <jats:sup>+<\/jats:sup>\n                      HCC, and that taurine in the tumor capsule modulates iCAF activity to influence tumor progression. The exploratory results provide mechanistic insights into MVI-related HCC progression and offer potential avenues for targeted therapeutic intervention of MVI\n                      <jats:sup>+<\/jats:sup>\n                      HCC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pmed.1004703","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T17:35:02Z","timestamp":1778866502000},"page":"e1004703","update-policy":"https:\/\/doi.org\/10.1371\/journal.pmed.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Spatial transcriptomic-metabolic features of tumor foci and tumor capsule in microvascular invasion with hepatocellular carcinoma: A spatial multi-omics 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epidemiology of liver cancer 2022: an emphasis on geographic disparities","volume":"137","author":"Q Li","year":"2024","journal-title":"Chin Med J"},{"issue":"10127","key":"pmed.1004703.ref002","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","article-title":"Hepatocellular carcinoma","volume":"391","author":"A Forner","year":"2018","journal-title":"Lancet"},{"issue":"11","key":"pmed.1004703.ref003","doi-asserted-by":"crossref","first-page":"101181","DOI":"10.1016\/j.jhepr.2024.101181","article-title":"Liver resection and transplantation in the era of checkpoint inhibitors","volume":"6","author":"P Tabrizian","year":"2024","journal-title":"JHEP Rep Innov Hepatol"},{"issue":"4","key":"pmed.1004703.ref004","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41571-024-00868-0","article-title":"Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma","volume":"21","author":"JM Llovet","year":"2024","journal-title":"Nat Rev 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Plasma proteomic signature for preoperative prediction of microvascular invasion in HCC. 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Hao","year":"2021","journal-title":"Cell"},{"issue":"1","key":"pmed.1004703.ref016","doi-asserted-by":"crossref","first-page":"4594","DOI":"10.1038\/s41467-022-32283-3","article-title":"A single-cell atlas of the multicellular ecosystem of primary and metastatic hepatocellular carcinoma","volume":"13","author":"Y Lu","year":"2022","journal-title":"Nat Commun"},{"issue":"1","key":"pmed.1004703.ref017","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1186\/s12885-024-12065-4","article-title":"Knockdown of ribosome RNA processing protein 15 suppresses migration of hepatocellular carcinoma through inhibiting PATZ1-associated LAMC2\/FAK pathway","volume":"24","author":"T Pan","year":"2024","journal-title":"BMC Cancer"},{"issue":"6","key":"pmed.1004703.ref018","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1097\/HEP.0000000000000269","article-title":"SERPINA12 promotes the tumorigenic capacity of HCC stem cells through hyperactivation of AKT\/\u03b2-catenin 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Santacatterina","year":"2025","journal-title":"bioRxiv"},{"issue":"3","key":"pmed.1004703.ref022","first-page":"100141","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"T Wu","year":"2021","journal-title":"Innovation (Camb)"},{"issue":"7938","key":"pmed.1004703.ref023","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41586-022-05400-x","article-title":"Liver tumour immune microenvironment subtypes and neutrophil heterogeneity","volume":"612","author":"R Xue","year":"2022","journal-title":"Nature"},{"issue":"1","key":"pmed.1004703.ref024","doi-asserted-by":"crossref","first-page":"4294","DOI":"10.1038\/s41467-023-39762-1","article-title":"Cancer-associated fibroblast classification in single-cell and spatial proteomics data","volume":"14","author":"L Cords","year":"2023","journal-title":"Nat Commun"},{"issue":"4","key":"pmed.1004703.ref025","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1038\/s41587-021-01091-3","article-title":"Identifying phenotype-associated subpopulations by integrating bulk and single-cell sequencing data","volume":"40","author":"D Sun","year":"2022","journal-title":"Nat Biotechnol"},{"issue":"24","key":"pmed.1004703.ref026","doi-asserted-by":"crossref","first-page":"10202","DOI":"10.1158\/0008-5472.CAN-10-2607","article-title":"A unique metastasis gene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients","volume":"70","author":"S Roessler","year":"2010","journal-title":"Cancer Res"},{"issue":"3","key":"pmed.1004703.ref027","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1007\/s00535-013-0791-4","article-title":"Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: a prospective study","volume":"49","author":"A Kudo","year":"2014","journal-title":"J Gastroenterol"},{"issue":"5","key":"pmed.1004703.ref028","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1136\/gutjnl-2014-308483","article-title":"Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study","volume":"65","author":"E Villa","year":"2016","journal-title":"Gut"},{"issue":"5","key":"pmed.1004703.ref029","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1021\/ac400009s","article-title":"Air flow-assisted ionization imaging mass spectrometry method for easy whole-body molecular imaging under ambient conditions","volume":"85","author":"Z Luo","year":"2013","journal-title":"Anal Chem"},{"issue":"16","key":"pmed.1004703.ref030","doi-asserted-by":"crossref","first-page":"5111","DOI":"10.1016\/j.jprot.2012.05.035","article-title":"Inclusive sharing of mass spectrometry imaging data requires a converter for all","volume":"75","author":"AM Race","year":"2012","journal-title":"J Proteomics"},{"issue":"14","key":"pmed.1004703.ref031","doi-asserted-by":"crossref","first-page":"2418","DOI":"10.1093\/bioinformatics\/btv146","article-title":"Cardinal: an R package for statistical analysis of mass spectrometry-based imaging experiments","volume":"31","author":"KD Bemis","year":"2015","journal-title":"Bioinformatics"},{"issue":"13","key":"pmed.1004703.ref032","doi-asserted-by":"crossref","DOI":"10.1093\/bioinformatics\/btr246","article-title":"Efficient spatial segmentation of large imaging mass spectrometry datasets with spatially aware clustering","volume":"27","author":"T Alexandrov","year":"2011","journal-title":"Bioinformatics"},{"issue":"1","key":"pmed.1004703.ref033","doi-asserted-by":"crossref","DOI":"10.1214\/ss\/1056397488","article-title":"Class prediction by nearest shrunken centroids, with applications to DNA microarrays","volume":"18","author":"R Tibshirani","year":"2003","journal-title":"Statist Sci"},{"issue":"4","key":"pmed.1004703.ref034","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41587-021-00830-w","article-title":"Robust decomposition of cell type mixtures in spatial transcriptomics","volume":"40","author":"DM Cable","year":"2022","journal-title":"Nat Biotechnol"},{"issue":"6190","key":"pmed.1004703.ref035","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1126\/science.1254257","article-title":"Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma","volume":"344","author":"AP Patel","year":"2014","journal-title":"Science"},{"issue":"5","key":"pmed.1004703.ref036","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1245\/s10434-019-07227-9","article-title":"Prognostic and therapeutic implications of microvascular invasion in hepatocellular carcinoma","volume":"26","author":"DJ Erstad","year":"2019","journal-title":"Ann Surg Oncol"},{"issue":"1","key":"pmed.1004703.ref037","doi-asserted-by":"crossref","first-page":"2415","DOI":"10.1038\/s41598-021-82058-x","article-title":"The clinical significance of microvascular invasion in the surgical planning and postoperative sequential treatment in hepatocellular carcinoma","volume":"11","author":"W Wang","year":"2021","journal-title":"Sci Rep"},{"issue":"1","key":"pmed.1004703.ref038","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12943-023-01876-x","article-title":"Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment","volume":"22","author":"C Ma","year":"2023","journal-title":"Mol Cancer"},{"issue":"5","key":"pmed.1004703.ref039","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1590\/0100-3984.2018.0123","article-title":"Microvascular invasion in hepatocellular carcinoma: is it predictable with quantitative computed tomography parameters?","volume":"52","author":"D Lahan-Martins","year":"2019","journal-title":"Radiol Bras"},{"key":"pmed.1004703.ref040","doi-asserted-by":"crossref","first-page":"1436131","DOI":"10.3389\/fimmu.2024.1436131","article-title":"Multi-transcriptomics analysis of microvascular invasion-related malignant cells and development of a machine learning-based prognostic model in hepatocellular carcinoma","volume":"15","author":"H Huang","year":"2024","journal-title":"Front Immunol"},{"issue":"15","key":"pmed.1004703.ref041","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.3390\/cells11152302","article-title":"A differentiation-related gene prognostic index contributes to prognosis and immunotherapy evaluation in patients with hepatocellular carcinoma","volume":"11","author":"J Xiao","year":"2022","journal-title":"Cells"},{"issue":"2","key":"pmed.1004703.ref042","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41419-022-04625-y","article-title":"Stathmin 1 is a biomarker for diagnosis of microvascular invasion to predict prognosis of early hepatocellular carcinoma","volume":"13","author":"Y Cai","year":"2022","journal-title":"Cell Death Dis"},{"issue":"1","key":"pmed.1004703.ref043","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13073-022-01055-5","article-title":"Human liver single nucleus and single cell RNA sequencing identify a hepatocellular carcinoma-associated cell-type affecting survival","volume":"14","author":"M Alvarez","year":"2022","journal-title":"Genome Med"},{"issue":"4","key":"pmed.1004703.ref044","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1172\/JCI200113712","article-title":"Glypicans: proteoglycans with a surprise","volume":"108","author":"J Filmus","year":"2001","journal-title":"J Clin Invest"},{"issue":"2","key":"pmed.1004703.ref045","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1006\/scdb.2000.0240","article-title":"Developmental roles of the glypicans","volume":"12","author":"B De Cat","year":"2001","journal-title":"Semin Cell Dev Biol"},{"issue":"7","key":"pmed.1004703.ref046","doi-asserted-by":"crossref","DOI":"10.3390\/biomedicines13071570","article-title":"Targeting glypican-3 in liver cancer: groundbreaking preclinical and clinical insights","volume":"13","author":"L Filippi","year":"2025","journal-title":"Biomedicines"},{"key":"pmed.1004703.ref047","doi-asserted-by":"crossref","first-page":"824208","DOI":"10.3389\/fonc.2022.824208","article-title":"Glypican-3: a novel and promising target for the treatment of hepatocellular carcinoma","volume":"12","author":"X Zheng","year":"2022","journal-title":"Front Oncol"},{"issue":"1","key":"pmed.1004703.ref048","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1007\/s12672-025-02295-8","article-title":"Relationship between retinol metabolism and hepatocellular carcinoma: a comprehensive analysis of Mendelian randomization, prognostic characteristic and experiment","volume":"16","author":"F Chen","year":"2025","journal-title":"Discov Oncol"},{"issue":"12","key":"pmed.1004703.ref049","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1158\/1535-7163.MCT-15-0274","article-title":"Severely impaired and dysregulated cytochrome P450 expression and activities in hepatocellular carcinoma: 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Wang","year":"2024","journal-title":"Cancer Res"},{"issue":"1","key":"pmed.1004703.ref068","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1007\/s12672-025-01879-8","article-title":"STMN1 regulates the stemness of gastric cancer cells by binding to HN1L to activate the STAT3 signaling pathway","volume":"16","author":"C Wei","year":"2025","journal-title":"Discov Oncol"},{"key":"pmed.1004703.ref069","doi-asserted-by":"crossref","first-page":"109413","DOI":"10.1016\/j.cellsig.2019.109413","article-title":"STAT3-CyPA signaling pathway in endothelial cell apoptosis","volume":"65","author":"Y Xie","year":"2020","journal-title":"Cell Signal"},{"issue":"12","key":"pmed.1004703.ref070","doi-asserted-by":"crossref","first-page":"2152","DOI":"10.1111\/j.1742-4658.2011.08132.x","article-title":"The chromosomal protein HMGN2 mediates lipopolysaccharide-induced expression of \u03b2-defensins in A549 cells","volume":"278","author":"L-X Deng","year":"2011","journal-title":"FEBS 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