The role of A20 as a master switch for the regulation of multiple distinct cell death pathways in hepatocarcinogenesis

• Applicant: Dr. Anne Schneider
• Subject Area: Cell Biology ; Gastroenterology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 457724578

The occurrence of liver cancer (hepatocellular carcinoma / HCC) is in the vast majority of cases the end result of chronic inflammatory processes of the liver, whereby inflammation is caused by cell death of hepatocytes. HCC is the third most common cause of cancer-related death worldwide with approximately 850,000 new cases per year. Unfortunately, a pharmacological treatment has not yet been established and highlights the need for new innovative research approaches. The tumor necrosis factor (TNF) signaling pathway has a particularly important role in the malignant degeneration of hepatocytes, since it regulates inflammatory processes as well as programmed cell death pathways. Based on novel preliminary findings I hypothesize that the ubiquitin-modifying molecule A20 is an essential modulator of cell death mechanisms and hepatocarcinogenesis in mice and humans. Therefore investigation of A20 in this context represents the focus of this present grant proposal.I took a major effort to generate new innovative tools and genetically modified mouse models which will allow me to answer the functional questions raised in this grant proposal. I first generated A20LPC-KO mice (liver parenchymal cells / LPC) in which apoptosis and necroptosis occur in parallel after LPS/TNF injection. Due to the fact that the kinase RIPK1 is involved in the regulation of both cell death mechanisms, I further generated A20/RIPK1LPC-KO mice that developed spontaneously HCCs. Surprisingly, HCC-development in A20/RIPK1LPC-KO mice is not only associated with increased apoptosis but also with hyperactivity of NF-kappaB. This result completely deviates from previous observations claiming that apoptosis-induced HCCs occur only under conditions with inhibited NF-kappaB activity. This opens up the possibility of obtaining a completely new view on the development of HCCs and thus possibly developing new therapeutic strategies. The investigation of the role of A20 in the newly generated mouse models will be done with state-of-the-art methods including in-vivo-2-photon live imaging of liver cell death. I further plan to functionally characterize novel molecular pathways regulating A20-dependent cell death and A20/RIPK1-dependent hepatocarcinogenesis. I will also systematically analyze how these newly characterized pathways influence HCC formation in human patients with chronic liver disease and correlate these findings with the clinical outcome. Upon completion of this study, I expect to reach a more comprehensive understanding of the role of A20 in the regulation of programmed cell death mechanisms with regard to the development of liver damage and liver cancer. In addition, I intend to explore new potential pharmacological targets with this approach as a basis of novel chemopreventive treatment strategies of liver cancer.

• DFG Programme: Research Grants