Sir Peter MacCallum Department of Oncology - Theses
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ItemInvestigating the regulation of metabolism by oncogenic transcription factors in liver cancer( 2022)Liver cancer remains one of the most lethal cancers worldwide. Therefore, understanding the pathogenesis of liver cancer is imperative to develop appropriate interventions to combat the disease. Although liver cancer is a heterogeneous disease at the genetic level, one of the unifying features is the deregulation of transcription factors. These transcription factors reprogram metabolism to promote liver tumourigenesis by mechanisms that are still poorly understood. In this thesis, I examined the role that two oncogenic transcription factors play in regulating metabolism and promoting liver growth. Firstly, I investigated the molecular mechanism by which the Hippo pathway nuclear effector, Yes-associated protein (Yap) reprograms lipid metabolism to promote hyperplastic liver growth. Secondly, I studied the effects of commonly amplified oncogene Myc, factor in regulating nucleotide metabolism to promote dysplastic liver growth. Thirdly, I examined the consequence of simultaneous expression of Yap and Myc in the liver to promote tumourigenesis. The central aim of my PhD project was to determine the role that oncogenic transcription factors, namely Yap and Myc play in regulating metabolism during pre-malignant growth and tumorigenesis. Liver cancer occurs in the context of chronic liver disease, where several stages of liver disease eventually develop into liver cancer. In this thesis, I examined the pre-malignant and tumour initiation stages of liver cancer using the zebrafish as an in vivo model. I asked several fundamental questions: 1) What are the key features of the liver tissue following activation of oncogenic transcription factors? 2) What metabolic pathways are regulated by oncogenic transcription factors to promote liver growth? 3) Can these metabolic pathways be targeted to suppress oncogenic liver growth? Using the zebrafish as an in vivo model, I found that: 1) Yap transcriptionally activates serum and glucocorticoid-regulated kinase 1 (SGK1), a regulator of the phosphoinositide 3-kinase (PI3K)- mechanistic target of rapamycin target complex 1 (mTORC1) pathway to promote activation of sterol regulatory-element binding protein (SREBP) lipogenic program. Consequently, this leads to hyperplastic liver growth, which was also characterised by lipid droplet (LD) accumulation in the hepatocytes. 2) Myc transcriptionally activates inosine monophosphate dehydrogenase (IMPDH) to promote de novo guanosine triphosphate (GTP) biosynthesis. This metabolic change promoted dysplastic liver growth, characterised by nucleolus expansion and hepatocyte dedifferentiation. 3) Simultaneous activation of Yap and Myc promote rapid liver tumourigenesis. Classical Yap and Myc gene signatures are upregulated in the liver tumour, which is sensitive to the standard of care chemotherapy, sorafenib. While activation of a single oncogene was not sufficient to induce tumourigenesis, activation of Yap or Myc was able to recapitulate aspects of pre-malignant liver growth. Specifically, hepatocyte-specific Yap activation promoted a fatty liver-like phenotype (steatosis). On the other hand, hepatocyte-specific Myc activation promoted dysplasia, similar to that typically found in the dysplastic nodules of cirrhotic livers. Simultaneous Yap and Myc activation caused rapid liver tumour development that models the initiation of liver tumorigenesis. All in all, I showed that oncogenic transcription factors reprogram metabolism to promote liver growth and tumourigenesis. I revealed that de novo lipogenesis (DNL) and de novo GTP biosynthesis are metabolic vulnerabilities in Yap or Myc driven cancer, respectively.