| Project Detail |
Non-alcoholic steatohepatitis: role of endothelial cells in progression to cancer
Non-alcoholic steatohepatitis (NASH) is a type of non-alcoholic fatty liver disease associated with fat build-up, inflammation and liver damage. It is dangerously progressive and a major risk factor for hepatocellular carcinoma. Changes in the gut–liver axis and in the organisation of liver cells play a role in the progression of NASH to hepatocellular carcinoma. These may be mediated by the single layer of endothelial cells lining the blood vessels that regulates the exchange of substances between the bloodstream and surrounding tissues. The ERC-funded CONNASHION project will investigate this using novel spatial sorting strategies together with advanced transcriptomics, phosphoproteomics and imaging to better understand protein signalling in the liver vasculature.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. |
