BEC specific activities of EGFR in liver disease

The liver is the bodys metabolic powerhouse. It filters blood, removes toxins, absorbs nutrients, and stores essential vitamins, sugars, fats, and iron. Diets high in fat and sugar but low in vitamins and fibercommon in many fast-food productscan lead to excessive fat accumulation in the liver, known as liver steatosis or Metabolic dysfunction-associated steatotic liver disease (MASLD). In response, liver cells begin to proliferate and function abnormally, promoting fibrosis. Without lifestyle changes, steatosis can progress to irreversible cirrhosis and eventually liver cancer. The livers epithelial compartment consists of two main cell types: hepatocytes, large cells responsible for metabolic functions, and biliary epithelial cells, smaller cells that produce bile and line the bile ducts. These cells are not fixed in their identity. When biliary epithelial cells are damaged-as happens during liver steatosis-, hepatocytes can reprogram themselves and adopt biliary characteristics. This process, known as hepatobiliary plasticity, is crucial for liver repair and regeneration. However, dysregulated and prolonged plasticity can drive the development of liver cancers. One of the gene frequently deregulated in steatosis and in liver cancer is the epidermal growth factor receptor (EGFR). EGFR sits on the cell surface where it receives growth signals from the outside and tells the cell what to do, i.e. to become bigger, to store nutrients or to divide. In this study, we will use state of the art experimental models to remove EGFR or modulate the activity of EGFR in either hepatocyte or biliary epithelial cells. Next, we will see if under these circumstances, the liver disease still occurs or if the liver remains healthy. In addition, to dissect how different liver cell types behave and communicate under disease conditions, we will apply single-cell RNA sequencing, allowing high-resolution analysis of thousands of individual cells present in the liver. This FWF-funded project will deepen our understanding of liver diseases and our results will be used to predict new pharmacological therapies. In addition, our findings on biliary epithelial cell biology will support the development of novel strategies for managing cholangiopathies, a group of bile duct diseases that often lead to liver failure and currently lack curative therapies. Insights into hepatobiliary plasticity might be relevant not only for cancer studies, but also for liver regeneration purposes.