The Cox laboratory

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 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 Cox laboratory 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 Cox laboratory's previous studies have taken advantage of chemical screens to identify that Nrf2 activation stimulates liver growth. More recently, the Cox laboratory combined novel metabolomic and transcriptomic strategies to discover that Yap reprograms nucleotide biosynthesis to fuel anabolic growth in cancer. Moving forward, the 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.

Unlike most human organs, the liver exhibits the remarkable capacity to regenerate. The process of liver regeneration is multifaceted, as it requires a complex tissue comprised of multiple cell types to sense the extent of injury and mount an appropriate compensatory regrowth response. However, despite decades of research, the molecular underpinnings of liver regeneration are poorly understood. Consequently, there is a need to better understand the molecular and cellular mechanisms that initiate liver regeneration. Nrf2 is a transcription factor that plays a pivotal role in the cell’s adaptation to stress. We previously identified that stimulation of the Nrf2 pathway upon liver injury facilitates regeneration.

Recently, the Cox laboratory has pioneered the use of integrated metabolomic and transcriptomic approaches in zebrafish to identify how metabolic remodelling impacts organ growth. We now have preliminary evidence that Nrf2 plays a key role in metabolic remodelling upon liver injury and is required for liver regeneration. Therefore, we are uniquely positioned to examine the mechanism by which Nrf2 remodels metabolism to fuel liver regeneration. This project will deliver new insights into the fundamental biological question of how metabolic remodelling is coordinated with tissue growth and regeneration. 

Building on these studies, the Cox laboratory currently has research projects that aim to determine the role that Nrf2 plays in adaptive metabolic remodelling during regeneration; characterize a new injury model in zebrafish that recapitulates chronic liver disease; and elucidate the dynamics of liver regeneration at the cellular level by in vivo imaging.