Interplay of cell proliferation and tissue remodelling in colorectal cancer

Q Science (General);R Medicine (General);RB Pathology

Halim, Silvia ; Vazquez, Alexei

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: 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.;   

Others  :  http://theses.gla.ac.uk/40975/1/2019halimphd.pdf

来源: University of Glasgow

【 摘 要 】

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 immunecell 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.