Elucidating How MLH1 Loss Regulates a Metabolic Phenotype in Endometrial Cancer
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Endometrial cancer is the fourth most common cancer in women and the most common gynaecological malignancy in the developed world. No new systemic treatments for endometrial cancer have been developed in recent years and its incidence is expected to double over the next decade. As such, there is a need to better understand key molecular pathways that are altered in the disease and could be targeted by novel treatments. The DNA MMR pathway is lost in approximately 30% of endometrial cancers. A small proportion of these are caused by germline mutations in one of the four MMR genes, however, the majority result from the epigenetic silencing of MLH1. Recently, our lab has shown that MLH1-deficient cells demonstrate a mitochondrial phenotype characterised by reduced OXPHOS, reduced mtDNA copy number and Complex I inhibition. OXPHOS-deficient cells must adapt their metabolism to compensate for energy defects and the inability to efficiently use the tricarboxylic acid cycle to generate energy. We hypothesise that this altered metabolism is driving tumourigenesis by increasing the tumour cells' metastatic potential. In this PhD we aimed to further investigate the influence MLH1 loss has on cellular metabolism using MLH1 positive and negative paired endometrial cell lines. Ultimately, we aim to understand whether altered metabolism in MLH1-deficient endometrial cancer may be therapeutically targeted.
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Gibson, ACollections
- Theses [4231]