Defining the clinical importance of epithelial-stroma-immune signalling in colorectal cancer using a molecular pathology approach

With current standard-of-care treatments, approximately 20% of stage II and 36% of stage III colon cancer (CC) patients will experience disease relapse following surgery. Molecular and histological subtyping of CC has identified a poor-prognostic group of patients characterised by high levels of epithelial-to-mesenchymal transition (EMT) signalling and an abundance of stroma (particularly fibroblasts) in their tumour microenvironment. To date, there has been inconsistent data regarding the benefit of standard chemotherapy in these patients with high-fibroblast (HiFi) tumours. Additionally, there is limited understanding of the specific biological signalling driving relapse in HiFi tumours. This study provides evidence to support the hypothesis that the EMT signalling seen in the poor-prognostic CC patients is due to increased levels of stromal cells present in their tumour samples, rather than increased epithelial cells undergoing EMT. A number of previously defined prognostic assays for CC identify these HiFi tumours, although when the HiFi group is assessed on their own, previously-defined prognostic biology fails to stratify patients based on relapse. To address this, work presented here describes the development, testing and independent validation of a novel seven-gene HiFi-specific prognostic signature.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

Queen's University Belfast

Year dc:date.issued

2021

Author dc:creator

• McCorry, Amy

Advisors dc:contributor.advisor

• Lawler, Mark
• Dunne, Philip
• Salto-Tellez, Manuel

• Cancer
• colorectal cancer
• colon cancer
• cancer-associated fibroblasts
• tumour microenvironment
• tumour stroma
• immune modulation
• antigen processing and presentation
• polyinosinic:polycytidylic acid
• poly(I:C)
• toll-like receptor 3
• TLR3
• gene expression signature
• prognostic signature
• epithelial–mesenchymal transition
• EMT
• molecular pathology
• STAT1
• translational

Language dc:language

eng

Identifier

oai:pure.qub.ac.uk/portal:studenttheses/1dfbf9c7-d497-40c7-8e7e-2f93dd3191f2

OAI identifier oai:identifier

oai:pure.qub.ac.uk/portal:studenttheses/1dfbf9c7-d497-40c7-8e7e-2f93dd3191f2