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Title: Single cell RNA-sequencing in the upper gastrointestinal tract
Author: Owen, Richard Peter
ISNI:       0000 0004 7654 3044
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Barrett's oesophagus is a precursor of oesophageal adenocarcinoma. In this common condition, squamous epithelium in the oesophagus is replaced by columnar epithelium in response to chronic acid reflux. Barrett's oesophagus is highly heterogeneous and its relationships to normal tissues are unclear. In this thesis, I investigate the cellular complexity of Barrett's oesophagus and the upper gastrointestinal tract using RNA-seq of single cells from multiple biopsies from six patients with Barrett's oesophagus and two patients without oesophageal pathology. I show that cell populations in Barrett's oesophagus, characterised by LEFTY1 expression, exhibit a profound transcriptional overlap with oesophageal submucosal gland cells, but not with gastric or duodenal cells. Additionally, SPINK4 appears to mark cells that precede morphologically identifiable goblet cells in Barrett's oesophagus, potentially aiding the identification of metaplasia. Then, using a machine learning-based approach to improve the accuracy of single nucleotide variant identification in single cell RNA-seq data ('snv.predict'), I show the mutational profiles and genetic relationships of cells in Barrett's oesophagus, demonstrating clonal phenotype heterogeneity and a common mutational link between Barrett's oesophagus and oesophageal submucosal glands. Finally, with the help of modifications designed to improve the practicality of plate based single cell RNA-seq in clinical science, I identify an adaptive-to-innate immune switch in tumour cells from a single patient with oesophageal adenocarcinoma treated with immunotherapy (anti PD-L1), as part of a clinical trial.
Supervisor: Lu, Xin ; Middleton, Mark Sponsor: Oxford NIHR Biomedical Research Centre ; Oxford Health Services Research Committee ; Ludwig Institute for Cancer Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available