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Title: Exploring novel aspects of choline phospholipid metabolism in cancer using metabolomics
Author: Lau, Chung Ho
ISNI:       0000 0004 5918 4270
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
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Abnormal metabolic phenotypes can be a powerful resource for drug and biomarker discoveries. In this thesis, a metabolomic approach was used to examine several aspects of tumour metabolism with potential clinical applications. In the first part, the metabolic consequences of PIK3CA mutation in MCF10A breast cells were assessed. PIK3CA mutation is oncogenic, and is important for disease progression in many breast tumours. Increased glutaminolysis, fatty acid synthesis, pyruvate entry into the TCA cycle, and decreased glycerophosphocholine (GPC) were identified to be the most prominent phenotypes following knock-in PIK3CA mutation in MCF10A cells. GPC has long been reported as a potential marker for disease progression; however, its functional role in cancer remains unclear. Glycerophosphodiester phosphodiesterase is responsible for the hydrolysis of GPC into choline and glycerol-3 phosphate (G3P), and EDI3 is a member of the glycerophosphodiester phosphodiesterase family associated with metastasis in endometrial cancer patients. Through metabolomic analysis of tumour cell models, EDI3 silencing was found to increase GPC levels and the GPC: phosphocholine ratio. Also, it was demonstrated that EDI3 had an impact on a broader spectrum of metabolic phenotypes, and effects on glycolysis and fatty acid synthesis were also observed. Finally, using 1H HR-MAS-NMR, changes in levels of choline phospholipid metabolites following Colony stimulating factor 1 receptor (CSF1R) inhibitor treatment were investigated in a mouse pancreatic tumour model. CSF1R is important for growth signalling of macrophages in tumours. Phosphocholine levels were found to be associated with disease progression and CSF1R inhibitor treatment. Collectively, these findings highlight a number of novel factors in choline phospholipid metabolism that may be important to tumourigenesis and the development of cancer biomarkers, including the role of glycerophosphodiester phosphodiesterase and macrophage-tumour interaction.
Supervisor: Keun, Hector ; Lam, Eric ; Woscholski, Rudiger ; Barter, Laura Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available