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Cell circuits as targets and biomarkers for liver disease and cancer prevention

Periodic Reporting for period 3 - HEPCIR (Cell circuits as targets and biomarkers for liver disease and cancer prevention)

Reporting period: 2019-01-01 to 2020-06-30

Chronic liver diseases such as liver cirrhosis and hepatocellular carcinoma (HCC) are major challenges for global health. HCC is the second leading and fastest rising cause of cancer death worldwide. According to the European Association for the Study of the Liver (EASL), the prevalence of liver diseases is ~6% in the EU (29 million individuals) and the associated mortality rate was estimated at 14.3 per 100,000 (70,000 deaths/year). Given the growing incidence of HCC, the economic burden will significantly increase in Western populations during the next decades. The limited availability of therapeutic options reflects our poor understanding of the molecular and clinical mechanisms involved in progression of liver disease. Chronic hepatitis C virus (HCV) infection is a main risk factor for HCC. Although HCC may be avoided by addressing the underlying cause in early stage disease, strategies to prevent HCC in patients with established cirrhosis and advanced fibrosis, in which the risk of HCC persists despite treatment of the underlying cause, are lacking. Indeed, even HCV cure does not eliminate the risk of HCC development when advanced fibrosis is already present. Since fibrosis/cirrhosis-driven carcinogenesis is the mechanism of HCC development common to all major etiologies, we are using HCV-induced liver disease as a model to decipher the pan-etiology sequence of molecular events underlying disease progression and HCC. Our own data provide solid evidence that HCV infection alters pathways implicated in liver disease progression, including cirrhosis deterioration, HCC development, as well as overall and liver-specific death. Thus, the molecular investigation of these pathways will identify key cell circuits for the understanding of the pathogenesis of liver disease and HCC in general, and as broadly applicable pan-etiology diagnostic and therapeutic targets. Using a novel patient-derived cell culture model system for liver disease biology combined with advanced functional genomics, novel animal models and clinical investigation, we aim to uncover the cell circuits that are of clinical relevance for liver disease progression and cancer. By providing novel targets and biomarkers for liver disease and HCC prevention, this project will have a marked impact on the management and prognosis of patients with liver disease and HCC.
The main objective of ERC ADG HEPCIR is to decipher the key factors and pathways responsible for the pathogenesis of liver disease progression ultimately leading to hepatocellular carcinoma (HCC). By using a novel cell culture model system mimicking the biological circuits of liver disease progression in patients, the team has (1) modelled the biological circuits of liver disease progression and HCC development, (2) identified drivers of liver disease progression and carcinogenesis and (3) started to set-up new mouse models that will enable to validate the impact of the findings in vivo.
By providing novel targets and biomarkers for liver disease and HCC prevention, this proposal will have a marked impact on the management and prognosis of patients with liver disease and HCC.
We have established model systems that recapitulate liver disease progression that are suited to both the identification of novel drivers as well as the discovery of potential therapeutics and preventive strategies for liver disease as outlined in this report. Using HCV-induced liver disease as a model, HEPCIR will profoundly advance our currently very limited understanding of pathogenesis of liver disease and cancer in several ways. First, HEPCIR has identified key pathways and circuits for pathogenesis of liver disease that will be explored as biomarkers for progression of liver disease that are urgently needed, allowing the identification of patients who will require close clinical monitoring for early intervention of HCC. Second, the discovery of pathways that are of relevance for the development of advanced liver disease, has enabled the discovery of drug targets and the development of screening assays for drug development. Third, comprehensive gene expression analyses can be used not only for the identification of pathways involved in pathogenesis of liver disease and development of HCC, but also as a means to monitor efficacy of preventive or therapeutic approaches for liver disease and HCC. Fourth, the general impact of the identified molecular mechanisms can subsequently be validated and extended to alcohol- or HBV-induced injuries and hereditary liver diseases. The HEPCIR team is confident that with the completion of this program a panel of novel biomarkers and validated targets for liver disease and HCC prevention will be delivered, and that the program will have a marked impact on the management of patients with liver disease and HCC in Europe and beyond.