Spatial analysis identifies LAMTOR2 overexpression in hepatocellular carcinoma with vessels encapsulating tumor clusters.

Authors

Yoon Jung Hwang, San Ha Hwang, Min Ji Kang, Geon Woo Park, Hyeewon Seo, Hyejung Lee, Hyun Je Kim, Suk Kyun Hong, Haeryoung Kim

Published in

Hepatology international. Jun 25, 2026. Epub Jun 25, 2026.

Abstract

Vessels encapsulating tumor clusters (VETC) is a distinct angiogenic pattern in hepatocellular carcinoma (HCC). 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.
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.
Spatial transcriptomic analysis identified 39 genes upregulated in VETC-positive regions, with enrichment of angiogenesis, WNT/β-catenin, Hedgehog, and p53 signaling, epithelial-mesenchymal transition, and fatty acid metabolism pathways, and suppression of immune-related pathways. Among these, LAMTOR2, DPP4, ZNHIT1, and MLXIPL were consistently upregulated in VETC-positive regions compared to both VETC-negative and normal liver regions. LAMTOR2 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 LAMTOR2 upregulation in malignant hepatocytes, particularly within VETC-high subpopulations enriched for lipid degradation, fatty acid oxidation, and detoxification pathways.
VETC-positive HCC exhibits a distinct transcriptomic and metabolic profile. LAMTOR2, which is consistently upregulated in VETC-positive HCCs, may contribute to angiogenic and metabolic reprogramming, offering potential implications for therapeutic stratification in HCC.

PMID:
42350874
Bibliographic data and abstract were imported from PubMed on 26 Jun 2026.

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