Transcriptional reprogramming of metabolism in liver cancer

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  Project Leader
  Dr Andrew Cox

  andrew.cox@petermac.org

  View researcher's webpage

  +61 3 8559 5439

Project Details

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…

1. Identify mechanism by which Yap reprograms lipid metabolism in liver cancer.
2. Determine how Nrf2 reprograms amino acid metabolism to fuel liver cancer.
3. To perform boutique chemical screens for metabolic vulnerabilities in Yap and Nrf2-driven liver cancer.

Research Opportunities

This research project is available to Honours students to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Publications

1. 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.
2. 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.
3. 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 growth. Nat Cell Biol. 18(8):886-96.