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Background <p>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.</p> Methods <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.</p> Results <p>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, <i>LAMTOR2</i>, <i>DPP4</i>, <i>ZNHIT1</i>, and <i>MLXIPL</i> were consistently upregulated in VETC-positive regions compared to both VETC-negative and normal liver regions. <i>LAMTOR2</i> 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 <i>LAMTOR2</i> upregulation in malignant hepatocytes, particularly within VETC-high subpopulations enriched for lipid degradation, fatty acid oxidation, and detoxification pathways.</p> Conclusion <p>VETC-positive HCC exhibits a distinct transcriptomic and metabolic profile. <i>LAMTOR2</i>, which is consistently upregulated in VETC-positive HCCs, may contribute to angiogenic and metabolic reprogramming, offering potential implications for therapeutic stratification in HCC.</p> Graphical abstract <p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月25日

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

摘要

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Graphical abstract