The liver is an essential organ that plays a key role in organismal energy homeostasis, functioning as a metabolic hub coordinating digestion and nutrient storage. The liver exhibits dynamic metabolic plasticity, which is accomplished by transcription factors that co-ordinate nutrient status to an appropriate metabolic response. In the context of cancer, there is emerging evidence that oncogenic transcription factors reprogram metabolism to fuel anabolic tumour growth. The Andrew Cox laboratory is chiefly interested in two oncogenic transcription factors, namely Yap and Nrf2. Yap is a transcriptional co-activator that regulates organ growth and operates as the effector of the Hippo pathway, whereas Nrf2 is a transcription factor that plays a key role in the cells adaptive response to oxidative stress. Importantly, both Yap and Nrf2 are known to play a central role in liver cancer, however the downstream mechanisms are poorly understood.
The Andrew Cox lab uses zebrafish (Danio rerio) as a model due to their unique attributes such as the transparency of embryos, high fecundity and conservation with higher vertebrates, which facilitates phenotype-driven chemical and genetic screens. The Andrew Cox lab's previous studies have taken advantage of chemical screens to identify that Nrf2 activation stimulates liver growth. More recently, the Andrew Cox lab combined novel metabolomic and transcriptomic strategies to discover that Yap reprograms nucleotide biosynthesis to fuel anabolic growth in cancer. Moving forward, the Andrew Cox laboratory is focussed on understanding how Yap and Nrf2 regulate metabolism in cancer.
Building on these studies, we currently have research projects that aim to identify mechanism by which Yap reprograms lipid metabolism in liver cancer; determine how Nrf2 reprograms amino acid metabolism to fuel liver cancer; and to perform boutique chemical screens for metabolic vulnerabilities in Yap and Nrf2-driven liver cancer.