Transcriptional reprogramming of metabolism by Yap and c-Myc in liver cancer

Cox AG1,2

  1. Peter MacCallum Cancer Centre.
  2. University of Melbourne.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and among the most fatal cancer type, as few effective treatments are available. Although the pathophysiology of HCC has not been fully elucidated, the process clearly arises in the context of chronic liver disease brought on by environmental factors. In the lab, we use an combination of transcriptomic, metabolomic and imaging approaches in mutant and transgenic zebrafish to reveal mechanisms by which metabolic reprogramming fuels premalignant hyperplasia and tumourigenesis in vivo. We have recently focused our attention on the role that the oncogenic transcription factors Yap and c-Myc play in reprogramming metabolism. To this end, we have developed a zebrafish model of Yap-driven HCC that recapitulates human HCC at the histological and genetic level. Using this model we found that Yap remodels glucose and glutamine metabolism to enhance the anabolic biosynthesis on nucleotides required for rapid tissue growth. In parallel, we have taken advantage of an inducible zebrafish model of HCC, in which c-Myc is overexpressed specifically in hepatocytes upon exposure to doxycycline. We have used these models to identify oncogenic changes in metabolism and screen potential metabolic interventions for efficacy in suppressing Yap or c Myc driven hyperplasia and HCC. Our long term goal is to identify oncogene-specific metabolic vulnerabilities that can be exploited therapeutically to prevent or combat liver cancer.