Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - HepatoMetaboPath (Cellular and molecular mechanisms of metabolic immune activation triggering non-alcoholic steatohepatitis (NASH) and HCC)
Teaser
Chronic hepatitis in the liver is the main driver of liver cancer, the second most common cause for cancer related death in humans. Several different etiologies have been demonstrated to cause chronic liver disease with prominent inflammation including chronic viral infections...
Summary
Chronic hepatitis in the liver is the main driver of liver cancer, the second most common cause for cancer related death in humans. Several different etiologies have been demonstrated to cause chronic liver disease with prominent inflammation including chronic viral infections with Hepatitis B or C (HBV, HCV) but also chronic alcohol consumption or chronic high caloric diet in combination with a sedentary life style.
Due to the consumption of high caloric food combined with increased sedentary lifestyle, overweight and obesity incidence has grown rapidly in Western countries (e.g. USA, Europe) but notably also in developing countries (e.g. India, China), affecting both adults and children. Although chronic viral infections are still the leading cause for hepatocellular carcinoma (HCC), alcoholic steatohepatitis (ASH), non-alcoholic fatty liver (NAFL) and subsequent non-alcoholic steatohepatitis (NASH) have become important etiologies for HCC. We and others have generated and characterized several pre-clinical mouse models that enable studying the mechanisms of inflammation induced liver cancer (e.g. NASH development and NASH to HCC transition in the context of a metabolic syndrome). Remarkably, these models recapitulated several human pathophysiological hallmarks of inflammation induced HCC. It has become apparent that adaptive immune cells but also innate immune cells play an important role in driving HCC - but at the same time actively participate in tumor surveillance.
Of particular interest and as an overall objective in this context is to understand the key role of immune cells (e.g. adaptive immune cells; platelets) in regulating intrahepatic inflammation and metabolic reprogramming.
In the context of this ERC consolidator grant we aim to understand and identify the different kinds of innate and adaptive immune cells, their metabolism and their effect on the epigenetic and genetic rearrangement of liver cancer initiation and progression. We will elucidate the processes that can drive primary liver cancer like NASH induced HCC or intrahepatic cholangiocarcinoma (iCC) and have already identified novel targets to treat inflammation induced liver cancer (e.g. in the context of NASH).
Work performed
From the beginning of the project we have focused on the characterization of immune cells involved in the development of fatty liver disease and liver cancer. This resulted in the definition of so far unrecognized cells involved in liver cancer as well as molecules driving liver inflammation, metabolic reprogramming and pathology. As the most important result we have identified a novel target in the treatment of fatty liver disease and fatty liver disease to liver cancer – GpIba – and could show in a pilot clinical trial that platelet deactivation is an important driver of liver pathology (Malehmir et al., Nature Medicine 2019).
Final results
Our results open up novel therapeutic tools and targets to treat NASH and NASH to HCC transition. Moreover, we have identified a novel technology to investigate the metabolic reprogramming of hepatocytes and immune cells on single cell level in situ.