Interplay of cell proliferation and tissue remodelling in colorectal cancer

Halim, Silvia (2019) Interplay of cell proliferation and tissue remodelling in colorectal cancer. PhD thesis, University of Glasgow.

Abstract

Human cancers can be classified based on gene expression signatures quantifying the degree of cell proliferation and a feature we term tissue remodelling. Yet, specific factors regulating the gene expression programs of cell proliferation and tissue remodelling are not well understood. In this work, I address this question using colorectal cancer as a case study.

In an initial evaluation of clinical outcome prediction in the case study cohort, our classification based on cell proliferation and tissue remodelling signatures delivers a better patient stratification than a recently reported consensus molecular subtyping (CMS). Although the CMS scheme predicts a worse prognosis for patients with a mesenchymal signature (a feature that strongly overlaps with tissue remodelling), it cannot differentiate the remaining patients based on clinical outcome. I show that cell proliferation is the missing factor, which is associated with good prognosis.

In the analyses of specific factors driving the tissue remodelling programme, I identify transcription factor KLF4 and microRNA mir-22 as putative regulators. Concordant with KLF4 role in immune cell regulation, KLF4 activity scores are significantly higher in colorectal tumours with predicted myeloid cells infiltration, suggesting its association with myeloid cell infiltration and poor prognosis in colorectal cancer. However, mir-22 is not associated with immune
cell infiltration, suggesting it may be expressed in the tumour stroma as well.

Lastly, I propose a network that may be regulated by IRF8, SPI1, KLF4 and mir-22 in monocyte differentiation and in colorectal cancer. The correlation analysis suggests a negative feedback loop, whereby mir-22 may repress Irf8 gene to control the rate of IRF8 transcription.

Taken together, I have identified specific regulators driving remodelling processes and their association with immune cell infiltration. In the future, it will be beneficial to conduct further studies to understand the mechanisms driving myeloid cell infiltration in colorectal cancer, particularly to propose treatments for patients exhibiting poor prognosis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Most of the results presented in chapters 3 and 4 of the thesis have been published in the work titled “Analysis of cell proliferation and tissue remodelling uncovers a KLF4 activity score associated with poor prognosis in colorectal cancer” in British Journal of Cancer.
• Keywords: colorectal cancer, patient stratification, supervised clustering, cell proliferation, tissue remodelling, immune cell infiltration, myeloid cell, transcription factor, transcriptional activity, inference model, microRNA, KLF4, mir-22, IRF8, SPI1, PU.1.
• Subjects: Q Science > Q Science (General); R Medicine > R Medicine (General); R Medicine > RB Pathology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cancer Sciences > Beatson Institute of Cancer Research
• Supervisor's Name: Vazquez, Dr. Alexei
• Date of Award: 2019
• Depositing User: Dr Silvia Halim
• Unique ID: glathesis:2019-40975
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 30 Jan 2019 12:35
• Last Modified: 05 Mar 2020 22:13
• Thesis DOI: 10.5525/gla.thesis.40975
• URI: https://theses.gla.ac.uk/id/eprint/40975

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