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Title: Investigating the cooperation of APC and KRAS mutations in colorectal cancer
Author: Gay, David Michael
ISNI:       0000 0004 7223 552X
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2018
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Colorectal Cancer (CRC) progresses in a stepwise manner accumulating mutations in particular signalling pathways. Despite our knowledge of the genetic progression of the disease, the resulting phenotypes of the different mutation combinations remains poorly understood. I used genetically engineered mouse models to investigate the cooperation of two frequent early mutations - loss of the tumour suppressor gene APC and activating KRAS mutations, to try and identify potential therapeutic targets. Hyperactivated Wnt signalling is a hallmark of CRC, although efficacious therapies are limited. In chapter 3 I focussed on targeting this pathway at the level of β-catenin mediated transcription. I showed that deletion of BLC9 and BCL9l, two proteins involved in β-catenin mediated transcription, suppresses proliferation and the expression of a subset of Wnt target genes following loss of APC and KRAS activation. I showed that these two proteins are dispensable intestinal homeostasis. I also showed that deletion of BCL9 and BCL9l significantly accelerated tumour initiation. In chapter 4 I performed unbiased quantitative proteomics on crypt cultures from VillinCreER Apcfl/fl (APC) and VillinCreER Apcfl/fl KrasG12D/+ (APC KRAS) mice to identify deregulated signalling pathways between these two genotypes. I identified a ‘nutrient stress’ phenotype in APC KRAS crypts. I show that this might be driven by a significant increase in protein synthesis, since APC KRAS cells are trying to regulate their rates of protein synthesis via eIF2α signalling. In chapter 5 I investigated changes in the metabolomes between APC and APC KRAS cells. I show that APC KRAS crypt cultures are highly dependent on glutamine for growth and upregulate many genes involved in glycolysis and glutaminolysis. I show that APC KRAS cells are metabolically flexible and also highlight the role the environment plays in metabolic phenotypes. Overall, I have shown that intestinal epithelial cells with high-Wnt and high-MAPK signalling are sensitive to Wnt inhibition. I have also shown that these two signalling pathways cooperate to drive increased protein synthesis and deregulated metabolism to fuel proliferation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: RC Internal medicine