Vascular Control of NASH Progression

Non-alcoholic steato-hepatitis (NASH) is a major risk factor for hepatocellular carcinoma (HCC), the 6th most common cause of cancer-related death worldwide.

The transition among different NASH stages to HCC stems from the complex interaction of multiple factors, including gut-liver axis modifications and a progressive dis-architecture of the liver parenchyma.The central role of endothelial cells in regulating the metabolic crosstalk along the gut-liver axis and in shaping the spatial organization of the liver parenchyma suggests a potential vascular control of NASH progression.

However, the possibility to precisely define the endothelial contribution is restrained by the limited ability to correlate gene expression profiling and functional readout, such as protein phosphorylation, with the complex morphological modifications occurring during NASH.To overcome these limitations, we combined innovative “spatial sorting” strategies with transcriptomics and quantitative phosphoproteomics, providing the first draft of the anatomical organization of proteins signaling in the liver vasculature.

Moreover, we unambiguously identified tyrosine phosphorylation – the main target of the anti-angiogenic therapy (ATT) – as one of the most spatially regulated signaling event.Building on this expertise, we will combine spatial sorting strategies in gut and liver with mouse models of NASH progression and advanced imaging modalities to pursue the following aims:1.

Provide a spatiotemporal characterization of the gut and liver vasculature undergoing NASH development.2. Dissect the vascular determinants of NASH progression.3.

Identify the molecular mechanisms underlying the synergistic effect between AAT and immune checkpoint inhibition.Together, our results will lay the foundation for understanding the molecular basis of a synergistic AAT and immune therapy in HCC, and help to identify novel prognostic markers as well as potential therapeutic targets.