Integrative transcriptome profiling elucidates molecular and immunovascular characteristics of macrotrabecular HCC

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BACKGROUND AND AIMS: Recent advances in single-cell RNA sequencing (scRNA-seq) technologies have enabled us to clarify gene regulatory networks and immune cell compositions. In this study, the integration of large-scale bulk and single-cell datasets refined HCC classification and shed light on the characteristics of its aggressive subtype. APPROACH AND RESULTS: Single-cell analysis of 228,564 live cells from 6 scRNA-seq datasets identified 5 major clusters of HCC cells with high mitotic activity (cluster 1), activated Wnt/β-catenin signaling (cluster 2), elevated glycolysis (cluster 3), and lipogenesis (clusters 4 and 5). Aggressive HCC subtype defined in bulk RNA-seq analysis of 691 tumor samples comprised a combination of cluster 1 with clusters 3, 4, or 5. Gene regulatory network analysis and gene set enrichment analysis highlighted the essential roles of p53 and MYC in aggressive HCC/cluster 1, and cell composition analysis elucidated T cell depletion as an immune resistance mechanism. In a syngeneic mouse model, Trp53 knockout and MYC overexpression caused high mitotic, tumorigenic, and metastatic phenotypes, characterized by a macrotrabecular pattern, vascular encapsulation, and T cell exclusion. Angiogenesis inhibition disrupted macrotrabecular/vascular encapsulation formation, resulting in T cell recruitment, and its combination with immune checkpoint blockade achieved remission. CONCLUSIONS: Single-cell analysis has deepened our understanding of the molecular mechanism and tumor microenvironment in aggressive HCC. The combination of targeting tumor vasculature and blocking immune checkpoints represents a promising therapeutic strategy for this subtype.

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