Dissertation

Investigating and Modelling Early Upper Gastro-Intestinal Neoplasia

White, Michael Joseph

2022

Overview

In recent years, gastro-oesophageal cancers have increased in incidence in the western world with no known cause. Barrett's oesophagus (BO) is a premalignant lesion induced by chronic biliary reflux. The cell of origin of BO has been greatly contested yet elusive. Non-dysplastic BO is a poorly understood but highly heterogeneous metaplastic tissue with deranged differentiation and a high incidence of early P53 mutations. Intestinal metaplasia (IM) is an internationally accepted defining criterion for BO diagnosis. In this thesis, I have examined the role of early P53 mutation in the development of gastro-oesophageal cancers by using a combined P53 mutant transgenic mouse in combination with a biliary reflux model. Although gastric cancers did not consistently occur, I found evidence that P53 mutations may potentiate inflammation in non-dysplastic BO. Further investigation of BO cellular complexity using sc-RNA-seq also found that BO shared transcriptional similarity with a subset of oesophageal cells, but not with gastric or duodenal cells, and identified a number of potential biomarkers. Lastly, I have developed organoid models for BO, and demonstrated their ability to differentiate into cell populations see in the scRNA-seq data. In conclusion, my findings reveal a striking similarity between normal OSG cells and BO cells with the high expression of LEFTY1 and TFF3. I identify potential early markers for goblet cell differentiation, SPINK4 and ITLN1 and OLFM4 expression as a marker of BO progenitor cells, which may have clinical implications.

• Publisher: ProQuest Dissertations & Theses