Pathological vessel remodelling in hepatocellular carcinoma: a single cell and spatially resolved transcriptome and interactome study to identify new targets

The characteristic vascular changes in hepatocellular carcinoma (HCC) are very distinct from those in other cancers. The liver becomes almost exclusively vascularised by hepatic arteries, while activation of different cell types in liver sinusoids result in microvascular capillarization. As a result, exchange of oxygen is impaired, aggravating tumor hypoxia and further fueling HCC growth. In a previous study, the host lab showed that interrupting this cycle with targeted therapies induces vessel normalization, reduces hypoxia, and inhibits HCC in preclinical models – establishing the importance of this liver vascular remodelling and highlighting the therapeutic potential of inhibiting these vascular changes. However, the molecular mechanisms underlying vascular remodeling in HCC remain poorly studied, likely explaining why current anti-angiogenics work poorly in HCC patients. High-throughput single-cell RNA-seq and Spatial Transcriptomics allows comprehensive, systematic profiling of the vascular cell types, their spatial relationships and molecular cross-talk (interactome), contributing to HCC, which has never been done before. Using this state-of-the-art profiling combined with targeted techniques, I will investigate the cellular dynamics and molecular mechanisms that govern the extreme vascular cell remodelling in HCC. Identification and validation of maladapted cellular pathways in vascular cell types in HCC, could reveal novel candidate therapeutic targets in HCC.