SFB-P04RE: Stat3 Signaling in Inflammation-Induced Liver Cancer (Robert Eferl)

The research interest concentrates on the role of Stat3 in hepatoprotection and liver cancer. The function of Stat3 in chemically-induced liver cancer is investigated in mice with conditional deletion of Stat3 in hepatocytes and cholangiocytes. Loss of Stat3 led to reduced size and multiplicity of liver tumors induced by the carcinogen Diethylnitrosamine (DEN) pointing to an oncogenic function of Stat3 in chemically-induced hepato-carcinogenesis. Moreover, intestinal cancer models have been established to investigate if Stat3 acts oncogenic in tumor types other than hepatocellular carcinoma. These studies revealed an unexpected anti-oncogenic function of Stat3 in intestinal tumor progression. The role of Stat3 in hepatoprotection and inflammation-induced liver cancer is investigated in Mdr2 knock-out (Mdr2-/-) mice. Mdr2-/- mice display chronic liver damage and liver cancer due to the production of toxic bile. Loss of Stat3 in hepatocytes and cholangiocytes of Mdr2-/- mice led to severe hepatic fibrosis, which is a prestage for hepatocellular carcinoma development. Global gene expression analysis revealed deregulation of bile acid biosynthesis and downregulation of IGF-1 and EGFR pathways, which have important hepatoprotective activity under cholestatic conditions. In addition to the conditional mouse models, SFB-P04RE is establishing a novel cancer mouse model that mimics the positive selection process of cancer development. This mouse model will be used to investigate the cooperativity between Stat3, Stat5 and NFB-signaling in cancer development.

SFB-P04RE (Robert Eferl) Stat3 functions in inflammation-induced liver- and intestinal cancer

RE contributes to the Research Area ‘JakStat in Cancer and Immune Surveillance’ and to the Technology Platform for ‘Gene-modified Mice’. The focus of SFB-P04RE is the role of Stat3 in hepatoprotection, liver cancer and intestinal cancer. A novel transgenic mouse technology will be established to identify cooperating partners and signaling pathways of Stat3 in tumorigenesis. Mice with conditional inactivation of Stat3 in hepatocytes and cholangiocytes (Stat3∆hc) have been generated using the AlfpCre transgene. Loss of Stat3 reduced size and multiplicity of liver tumors induced by the hepatocarcinogen diethylnitrosamine (DEN). The molecular basis for the oncogenic activity of Stat3 in liver cancer will be further investigated. The emphasis will be placed on Stat3 functions in hepatoprotection and regulation of the tumor microenvironment. Stat3∆hc mice have been crossed to Mdr2 knock-out (Mdr2-/-) mice to investigate the function of Stat3 in hepatoprotection and inflammation-induced liver cancer. Loss of Stat3 in hepatocytes and cholangiocytes of Mdr2-/- mice led to premature lethality associated with strongly aggravated hepatic fibrosis. The hepatoprotective activity of Stat3 signaling in cholestatic diseases and liver fibrosis will be further investigated. A conditional mouse model has been established to investigate the function of Stat3 in intestinal cancer. Conditional inactivation of Stat3 in intestinal epithelial cells reduced formation of early adenomas in APCmin mice but promoted tumor progression and invasiveness. The molecular mechanisms that modulate oncogenic and anti-oncogenic activities of Stat3 during intestinal tumor progression will be further investigated. A mouse model for investigation of the cooperativity between Stat3, Stat5 and NFκB-signaling in cancer will be established. This mouse model is based on the Multi-Hit technology. The establishment of Multi-Hit mice turned out to be challenging and required several pilot studies. Therefore, a “proof of principle” mouse model with three oncogenic H-ras effector mutants has been established. The knowledge and technical improvements derived from the “proof of principle” mouse model will be used to generate Multi-Hit mice for Stat3, Stat5 and NFκB-signaling.