The Metabolic Role of the Hippo Pathway in Liver Development and Cancer

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The Metabolic Role of the Hippo Pathway in Liver Development and Cancer

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Title: The Metabolic Role of the Hippo Pathway in Liver Development and Cancer
Author: Hwang, Katie Lee ORCID  0000-0002-0745-2558
Citation: Hwang, Katie Lee. 2015. The Metabolic Role of the Hippo Pathway in Liver Development and Cancer. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
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Abstract: Hepatocellular carcinoma (HCC) is a global health problem with poor prognosis and limited therapeutic options. While the clinical risk factors for HCC are well described, the precise molecular and metabolic mechanisms contributing to malignant transformation remain largely unknown. Recently, the Hippo signaling pathway has been identified as a key regulator of cellular proliferation, organ size, and tumorigenesis in numerous tissues, including the liver. However, the metabolic impact of the pathway in supporting liver growth and tumorigenesis has not been studied. The zebrafish, Danio rerio, has successfully been applied as a model to investigate signaling pathways important in organ development to model liver development and cancer. Here, we utilize the zebrafish to investigate the functional and metabolic roles of the Hippo pathway in liver development and cancer in vivo.
Using a transgenic zebrafish model with liver-specific activation of the transcriptional co-activator Yap, the downstream target of the Hippo pathway, we show Yap is functionally conserved in its ability to promote embryonic and adult hepatomegaly. These livers demonstrate signs of dysplasia and increased tumor susceptibility upon chemical carcinogen exposure. Using transcriptomic and metabolomic analysis, we discover that nitrogen metabolism is significantly altered in Yap-transgenic livers. Yap upregulates glutamine synthetase (Glul) expression leading to elevated steady-state levels of glutamine, which significantly contributes to its ability to enhance liver growth and de novo purine biosynthesis.
To further probe the functional and metabolic role of Yap prior to liver outgrowth, we utilize yap knockout zebrafish and heat-shock inducible transgenic zebrafish that modulate
Yap activity to examine early liver development. We show Yap is important for hepatoblast formation and expansion. Further, Yap modulates glucose uptake and glycolytic flux into de novo nucleotide synthesis. Overall, this dissertation reveals novel roles of Yap in cellular metabolism to support proliferation and growth by directing glucose into the building blocks of DNA in the context of development and cancer.
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