The tumour microenvironment in Oesophageal Adenocarcinoma

Abstract

Oesophageal Adenocarcinoma (OAC) is a lethal disease with a growing incidence worldwide and limited effective treatment options. Large clinical trials and incremental clinical improvements have led to five-year survival rates in England of only 15%. Large genome wide collaborative studies of the somatic mutations in oesophageal adenocarcinoma have not yet delivered clinically actionable targets for effective novel therapies. The cells of the tumour microenvironment in oesophageal cancer carry prognostic importance and modern randomised trials are targeting pro-cancer pathways and proteins from non-mutated, normal cells that form the bulk of the tumour microenvironment. In this thesis I describe the cells of the tumour microenvironment in oesophageal adenocarcinoma detected by single cell RNA sequencing(scRNAseq) and present potential targets for therapy. I begin by describing the current clinical and molecular understanding of oesophageal cancer and the urgent need for research. I demonstrate the strengths and limitations of current genomic and transcriptomic analyses and the rationale for employing new technology. I then demonstrate the utility of scRNAseq in identifying the cell types in a mixed population and identifying the marker genes and gene programs differentially expressed between cell types. I then present the first ever comprehensive cellular atlas of oesophageal adenocarcinoma. I go on to describe novel findings in cancer cells after neo-adjuvant therapy and, the potential implications for these findings in the context of current treatment controversies. Moving away from malignant cells, I use the gene programs identified to classify the tumour microenvironment in publicly available bulk RNA datasets and I describe the predicted in silico interactions between non-malignant and malignant cells of OAC. This analysis highlights cancer associated fibroblasts(CAFs) as key tumour promoting cells of the tumour micro-environment. Finally, I use scRNAseq to demonstrate abrogation of tumour promoting expression programs in cultured CAFs treated with repurposed PDE5 inhibitors.

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Identifiers

ORCID for Timothy Underwood: orcid.org/0000-0001-9455-2188

ORCID for Matthew Rose-Zerilli: orcid.org/0000-0002-1064-5350

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