In the Cox laboratory, we use zebrafish (Danio rerio) as a model system to study pathways that regulate liver growth during development, regeneration and cancer.
A central theme of this work is to understand how metabolic reprogramming fuels tissue growth.
Metabolic reprogramming by the Hippo/Yap pathway
The Hippo/Yap pathway is an evolutionarily conserved cascade that plays a fundamental role in governing organ size control, stem cell homeostasis and cancer. The Hippo/Yap pathway is regulated by a range of environmental cues, including nutrient status. Although many of the inputs into the Hippo pathway have been identified, less is known about the Yap target genes responsible for tissue growth. Using a combination of metabolomic and transcriptomic approaches in zebrafish, we have discovered that Yap reprograms glutamine metabolism in vivo to stimulate nucleotide biosynthesis and fuel premalignant liver growth.
Building on this initial investigation, we currently have research projects that aim to:
- Examine how Yap coordinates nutrient sensing to metabolic output in the liver.
- Elucidate the mechanisms by which Yap reprograms metabolism to fuel liver growth in the context of regeneration and cancer.
Role of Nrf2 and metabolic remodelling in liver cancer
Many of the major risk factors for developing liver cancer, such as alcohol, obesity, smoking and toxin exposure, have in common a role for oxidative stress. Nrf2 is a transcription factor activated by oxidative stress; it orchestrates an adaptive response by remodelling metabolism and promoting cytoprotection. Recent studies have identified that the Nrf2 pathway is frequently mutated in liver cancer (about 12 per cent of tumours). We have used transcriptomic and metabolic profiling in Nrf2-/- zebrafish to examine the role that Nrf2 plays in remodelling metabolism during liver development and regeneration.
Building on these preliminary studies, we currently have research projects that aim to:
- Generate a gain-of-function Nrf2 mutant (Nrf2D29H), frequently observed in cancer, and characterise the effect of this mutation on metabolic reprogramming.
- Examine how deregulation of Nrf2 remodels the metabolism to stimulate liver tumourigenesis.
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. Oct 22. * 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 growth. Nat 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 regeneration. Curr 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 injury. Cell 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 tumorigenesis. Cell. 151(7):1457-73.