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Using patient derived organoids to explore mechanisms of tumourigenesis in adenomatous polyposis syndromes

Walters, Angharad 2023. Using patient derived organoids to explore mechanisms of tumourigenesis in adenomatous polyposis syndromes. PhD Thesis, Cardiff University.
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Duodenal polyposis and cancer have become a leading cause of morbidity and mortality for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), yet the associated molecular mechanisms remain poorly understood. Current cellular models that might be used to improve understanding are limited. This study reports the development and characterisation of a novel duodenal model for adenomatous polyposis, using patient derived organoids to investigate putative drivers of duodenal polyposis. Thirty-eight duodenal organoid lines were established from FAP and MAP patients’ duodenal adenomas (n=16) and normal mucosa (n=22) tissues. The organoids were shown to largely recapitulate the originator tissues genetically and histologically, and to remain relatively stable in culture and during expansion using Cellesce’s (now Molecular Devices) patented bioprocessing technology. PIGA, a novel putative driver of duodenal tumourigenesis in FAP and MAP patients, was investigated in patient-derived PIGA mutant and PIGA knock-out CRISPR generated organoid lines. This confirmed complete ablation of GPI-anchors from the surface of epithelial cells as a consequence of PIGA mutation and suggested a potential novel mechanism driving polyp progression. RNA-sequencing data from FAP and MAP patient duodenal adenoma and normal mucosa tissues (FAP ad= 14, norm= 5; MAP ad= 15, norm= 8) were used to identify potential transcriptomic drivers of duodenal tumourigenesis. ANXA10 and FGFBP1 were identified and validated as having upregulated expression in an independent set of duodenal adenomas from FAP patients. They were investigated further in organoid lines revealing increased expression in both adenoma- and normal mucosa- derived lines, suggesting that organoid culture and/or expansion as well as tumourigenesis affected their expression. Novel drivers of duodenal tumourigenesis may represent targets for pharmaceutical prevention or treatment of duodenal polyposis, and organoid lines could be used in screening of candidate drugs to achieve this.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 1 March 2024
Last Modified: 01 Mar 2024 16:54

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