In the Cox laboratory, we use zebrafish (Danio rerio) as a model system to study the metabolic regulation of growth during embryonic development, regeneration and cancer.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and among the most fatal cancer types. 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, which conspire with oncogenic pathways to initiate tumourigenesis. One of the emerging hallmarks of cancer is reprogramming of metabolism. Our lab takes advantage of cutting-edge technologies including multiphoton microscopy, metabolomics, transcriptomics and chemical genetic screens to elucidate the molecular underpinnings of metabolic reprogramming in cancer.

Research projects

Transcriptional reprogramming of metabolism in liver cancer

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. My 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. Our work 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. Our previous studies have taken advantage of chemical screens to identify that Nrf2 activation stimulates liver growth. More recently, we combined novel metabolomic and transcriptomic strategies to discover that Yap reprograms nucleotide biosynthesis to fuel anabolic growth in cancer. Moving forward, my 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.
  • To perform boutique chemical screens for metabolic vulnerabilities in Yap and Nrf2-driven liver cancer.

Adaptive remodelling of metabolism during liver regeneration

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, we have 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, we currently have research projects that aim to…

  • To determine the role that Nrf2 plays in adaptive metabolic remodelling during regeneration.
  • To characterize a new injury model in zebrafish that recapitulates chronic liver disease.
  • To elucidate the dynamics of liver regeneration at the cellular level by in vivo imaging.

People

Anthony Karamalakis, Research Assistant
Marcos Sande Melón, Postdoctoral Fellow
Vicky Tan, PhD Research Student
Talhah Salmi, PhD Research Student
Athena Ong, PhD Research Student
Tara Tigani, Research Assistant
Mikaela Wong, Honours Student
Madeline Webb, Honours Student

Key publications

Salmi TM, Tan VWT, Cox AG* (2019). Dissecting metabolism using zebrafish models of disease. Biochem Soc Trans. 47(1):305-315. * Corresponding author. 

Cox AG*, Tsomides A, Yimlamai D, Hwang KL, Miesfeld J, Galli GG, Fowl BH, Fort M, Ma KY, Sullivan MR, Hosios AM, Snay E, Yuan M, Brown KK, Lien EC, Chhangawala S, Steinhauser ML, Asara JM, Houvras Y, Link B, Vander Heiden MG, Camargo FD, Goessling W (2018). Yap regulates glucose utilization and sustains nucleotide synthesis to enable organ growth. EMBO J. 37(22). pii: e100294. * Co-corresponding author.

Cox AG, Tsomides A, Kim AJ, Saunders D, Hwang KL, Evason KJ, Heidel J, Brown KK, Yuan M, Lien EC, Lee BC, Nissim S, Dickinson B, Chhangawala S, Chang CJ, Asara JM, Houvras Y, Gladyshev VN, Goessling W (2016). Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis. Proc Natl Acad Sci USA. 113(38):E5562-71.

Cox AG, Hwang KL, Brown KK, Evason KJ, Beltz S, Tsomides A, O'Connor K, Galli GG, Yimlamai D, Chhangawala S, Yuan M, Lien EC, Wucherpfennig J, Nissim S, Minami A, Cohen DE, Camargo FD, Asara JM, Houvras Y, Stainier DY, Goessling W (2016). Yap reprograms glutamine metabolism to increase nucleotide biosynthesis and enable liver growthNat Cell Biol. 18(8):886-96.

Cox AG, Goessling W (2015). The lure of zebrafish in liver research: regulation of hepatic growth in development and regenerationCurr Opin Genet Dev. 32:153-61.

Cox AG, Saunders DC, Kelsey PB Jr, Conway AA, Tesmenitsky Y, Marchini JF, Brown KK, Stamler JS, Colagiovanni DB, Rosenthal GJ, Croce KJ, North TE, Goessling W (2014). S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injuryCell Rep. 6(1):56-69.

Rosenbluh J, Nijhawan D, Cox AG, Li X, Neal JT, Schafer EJ, Zack TI, Wang X, Tsherniak A, Schinzel AC, Shao DD, Schumacher SE, Weir BA, Vazquez F, Cowley GS, Root DE, Mesirov JP, Beroukhim R, Kuo CJ, Goessling W, Hahn WC (2012). β-Catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesisCell. 151(7):1457-73.

Research programs

Positions available

PhD and Postdoc positions are available in the areas of research outlined above. Please contact Andrew Cox for further information.