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Title: Investigating right-sided colon cancer and the involvement of inflammation, the microbiome, and foetal stem cell-like plasticity
Author: Leach, Joshua
ISNI:       0000 0005 0286 8126
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2021
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Human right-sided colorectal cancer (CRC) has a poor prognosis and distinct mutational profile compared with left-sided CRC. Indeed right-sided CRCs are associated with BRAF mutations and aberrations in both the mismatch repair and TGFb signalling pathways, whilst left-sided CRCs are associated with APC and TP53 mutations. In chapter III I establish a mouse model of right-sided colon cancer driven by activation of BRAF and loss of TGFb-receptor signalling. Furthermore I confirm that this model reproduces a number of the key stereotypical clinicopathological behaviours observed in right-sided tumours in patients, particularly the lack of Wnt pathway activation. In chapter IV I show that these tumours, though lacking Wnt pathway activation, exhibit a foetal-like phenotype (Ly6a+). This phenotype, also recently recognised in the context of colitis associated intestinal regeneration, had initially been identified in the foetal intestine and characterised by the absence of Lgr5 expression and expression of markers including Ly6a. Following the identification of this epithelial differentiation status in the murine right-sided tumours, I also showed that this phenotype is present in patient derived right-sided CRCs and that the gene expression pattern associated with these murine tumours is predictive of the key clinicopathological features of right-sided disease. In chapter V and VI I show that this foetal-like phenotype is due to the direct activation of YAP1 by MAPK signalling, and that the phenotype is further amplified by microenvironmentally driven inflammation. Importantly I also confirm that the tumorigenic potential of this foetal-like epithelial population, whether driven by MAPK-dependent or independent mechanisms, is uniquely suppressed by epithelial TGFb signalling. Finally I also confirm that YAP1 activation is vital for the ongoing viability of these foetal-like epithelial populations and that they have unique growth requirements (e.g. prostaglandin E2) that potentially provide the possibility for novel targeted therapeutic strategies in patients with right-sided disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: RB Pathology ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)