Multiomics and multi-region spatial transcriptome analysis reveal cellular networks and pathways associated with HCC...

Area of Science:

• Oncology
• Tumor Microenvironment Research
• Molecular Pathology

Background:

• Hepatocellular carcinoma (HCC) presents diverse etiologies and molecular heterogeneity.
• High recurrence rates post-surgery limit survival, underscoring the need to understand the tumor microenvironment (TME).

Purpose of the Study:

• To investigate the complex TME in HCC.
• To explore cell type interactions within the TME and their role in HCC recurrence.

Main Methods:

• Multi-omics analysis including spatial and bulk RNA sequencing on HCC samples.
• Validation using immunofluorescence and multiplex immunohistochemistry.
• Analysis of the PLANet 1.0 cohort (NCT03267641).

Main Results:

• Identified extensive intra- and intertumour gene expression heterogeneity in HCC.
• Discovered a subset of INTS6+ endothelial cells (ECs) spatially colocalized with tumor cells in recurrent HCC.
• Found enrichment of INTS6+ ECs in microvascular invasion regions and a significant ANGPTL4-SDC1 interaction with tumor cells.

Conclusions:

• INTS6+ ECs are associated with microvascular invasion and tumor cells in recurrent HCC.
• These ECs may play a role in HCC disease recurrence.
• Targeting endothelial-tumor cell interactions within the TME presents a promising therapeutic strategy.