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

HCC is a highly vascular tumor, and many effective drug regimens target the tumor blood vessels. Prior bulk HCC subtyping data used bulk transcriptomes, which contained a mixture of parenchymal and stromal contributions. Using cell type–specific spatial transcriptomics techniques to separate cancer cells and endothelial cells applied to a set of 41 resected HCC tissue specimens, we report that the prior Hoshida bulk transcriptional subtyping schema is driven largely by an endothelial fraction, show an alternative tumor-specific schema has potential prognostic value, and use spatially paired ligand-receptor analyses to identify known and novel (LGALS9 tumor-HAVCR2 vessel) signaling relationships that drive HCC biology in a subtype-specific and potentially targetable manner. Our study leverages spatial gene expression profiling technologies to dissect HCC heterogeneity and identify heterogeneous sig- naling relationships between cancer cells and their endothelial cells. Future validation and expansion of these findings may validate novel cancer- endothelial cell interactions and related drug targets. We used cell type–specific spatial transcriptomics techniques (Nanostring GeoMx) to separate cancer cells and endothelial cells applied to a set of 41 resected HCC tissue specimens.