HCC spatial transcriptomic profiling reveals significant and potentially targetable cancer-endothelial interactions.

Area of Science:

• Genomics and Molecular Biology
• Cancer Research
• Translational Medicine

Background:

• Hepatocellular carcinoma (HCC) is a highly vascular tumor, with treatments often targeting tumor vasculature.
• Previous HCC subtyping relied on bulk transcriptomics, confounding tumor and stromal cell contributions.
• Understanding cellular heterogeneity is crucial for developing effective HCC therapies.

Purpose of the Study:

• To re-evaluate HCC transcriptional subtyping using cell type-specific spatial transcriptomic data.
• To identify novel signaling pathways between tumor and endothelial cells in HCC.
• To explore potential new therapeutic targets based on subtype-specific interactions.

Main Methods:

• Computational deconvolution and cell-cell interaction analyses were applied to spatial transcriptomic data.
• Data were derived from 41 resected hepatocellular carcinoma tissue specimens.
• Tumor-enriched and vessel-enriched fractions were analyzed for cell type-specific gene expression.

Main Results:

• The Hoshida bulk transcriptional subtyping schema for HCC is primarily driven by the endothelial cell fraction.
• An alternative tumor-specific subtyping schema demonstrates potential prognostic value.
• Spatially paired ligand-receptor analyses identified known and novel signaling relationships (e.g., LGALS9-HAVCR2) driving HCC biology.

Conclusions:

• Spatial gene expression profiling effectively dissects HCC heterogeneity and identifies cancer cell-endothelial cell signaling.
• Findings suggest subtype-specific and potentially targetable signaling relationships.
• Further validation may identify novel therapeutic targets for hepatocellular carcinoma.