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While VETC-positive HCC is associated with poor prognosis, it demonstrates improved responses to vascular-targeted therapies. However, the molecular signatures that define VETC-positive HCC remain elusive. This study employed spatial transcriptomics and single-cell RNA sequencing to characterize the molecular landscape of VETC-positive HCC and identify candidate biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using GeoMx Digital Spatial Profiling, we analyzed tumor and adjacent liver tissues from 24 HCC patients, focusing on VETC-positive, VETC-negative, or non-neoplastic liver regions. Differential gene expression and pathway enrichment analyses were performed. Candidate genes were further evaluated using immunohistochemistry, The Cancer Genome Atlas (TCGA) dataset, and single-cell RNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Spatial transcriptomic analysis identified 39 genes upregulated in VETC-positive regions, with enrichment of angiogenesis, WNT\/\u03b2-catenin, Hedgehog, and p53 signaling, epithelial\u2013mesenchymal transition, and fatty acid metabolism pathways, and suppression of immune-related pathways. Among these,\n                      <jats:italic>LAMTOR2<\/jats:italic>\n                      ,\n                      <jats:italic>DPP4<\/jats:italic>\n                      ,\n                      <jats:italic>ZNHIT1<\/jats:italic>\n                      , and\n                      <jats:italic>MLXIPL<\/jats:italic>\n                      were consistently upregulated in VETC-positive regions compared to both VETC-negative and normal liver regions.\n                      <jats:italic>LAMTOR2<\/jats:italic>\n                      demonstrated tumor-specific localization in TCGA dataset. Immunohistochemistry confirmed that peripheral accentuation pattern of LAMTOR2 expression was restricted to tumor cells and strongly correlated with RNA expression and VETC positivity. Single-cell RNA sequencing further revealed\n                      <jats:italic>LAMTOR2<\/jats:italic>\n                      upregulation in malignant hepatocytes, particularly within VETC-high subpopulations enriched for lipid degradation, fatty acid oxidation, and detoxification pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      VETC-positive HCC exhibits a distinct transcriptomic and metabolic profile.\n                      <jats:italic>LAMTOR2<\/jats:italic>\n                      , which is consistently upregulated in VETC-positive HCCs, may contribute to angiogenic and metabolic reprogramming, offering potential implications for therapeutic stratification in HCC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s12072-026-11115-2","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T17:23:21Z","timestamp":1782408201000},"page":"1150-1161","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial analysis identifies LAMTOR2 overexpression in hepatocellular carcinoma with vessels encapsulating tumor clusters"],"prefix":"10.1007","volume":"20","author":[{"given":"Yoon Jung","family":"Hwang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"San Ha","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Ji","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geon Woo","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyeewon","family":"Seo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyejung","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4467-0949","authenticated-orcid":false,"given":"Hyun Je","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0020-6215","authenticated-orcid":false,"given":"Suk Kyun","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4205-9081","authenticated-orcid":false,"given":"Haeryoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"issue":"3","key":"11115_CR1","first-page":"229","volume":"74","author":"F Bray","year":"2024","unstructured":"Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. 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