Understanding how fatty liver disease reprograms liver cancer cells

Liver cancer is a deadly disease and its occurrence is growing worldwide. Notably, the rise in obesity caused by modern western diet (high fat, high sugar, high cholesterol) is correlated with an increased cancer incidence and mortality. Western diet causes chronic fatty liver disease that progresses to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and eventually liver cancer. However, how fatty liver disease promotes tumor formation is not known but important to understand if we want to halt the increase in this devastating disease. Several mechanisms have been proposed to explain how NASH triggers liver cancer including an increased mutation rate, fibrosis driven hepatocyte proliferation, and inflammation driven cancer cell phenotypes. However, these mechanisms are not sufficient to explain how senescent hepatocytes present in NASH transform into liver cancer. We recently developed a new model system in mice to study how NASH promotes liver cancer. Interestingly, we found that NASH directly triggered the reprogramming of cells expressing activated cancer genes (oncogenes). We are now investigating the molecular mechanisms by which NASH converts a phenotypically normal cell into a cancer cell. We expect that our research will help to identify new avenues to suppress the initiation of liver cancer and to fight against its progression.