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Title: Monocyte dynamics in breast cancer
Author: Robinson, Amy Clare
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2019
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Work in mouse models has highlighted a role for classical monocytes in promoting cancer. Furthermore, recent human studies show that blood monocytes in a variety of cancers exhibit transcriptional shifts from steadystate. However, it remains unclear exactly how cancer affects monocyte homeostasis and function. To study monocyte regulation in cancer, blood was analysed over the course of tumour progression in mice that develop spontaneous mammary cancers (MMTV-PyMT). Monocyte production, release and turnover were investigated by colony forming unit assays and BrdU tracing. RNA extracted from blood and bone marrow (BM) monocytes was sequenced. Next, gene expression was compared with monocytes in human breast cancer patients. Finally, Accessibility of Transposase Assay (ATAC) sequencing was used to investigate chromatin conformation of monocytes in human breast cancer. In mice, blood monocyte numbers were significantly increased in late cancer compared with controls. This increase was equivalent in both classical and non-classical monocytic populations. The proliferation of classical monocytes in the BM was increased in cancer, whereas monocyte release and half-life in the circulation were unaltered. Classical monocytes in mice with late stage cancer featured down-regulation of genes involved in interferon response, cytokine stimulus, and antigen-cross-presentation. These changes were conserved across cells in the BM and blood and across two mice strains. There were no orthologous genes or functional pathways with humans whom had early stage cancer. In patients with early breast cancer, there was an upregulation of NFKB pathway signalling in circulating monocytes. Findings by ATACseq were inconclusive but established the use of this technique in this context. This study suggests that the cancer manipulates the transcriptional landscape of monocytes. The effects in mice may be secondary to haematopoietic stress. This contrasts with humans, where it seems that conditioning of circulating monocytes results in a pro-tumoural phenotype. Due to the lack of orthologous changes in mice, further work needs to be undertaken in humans. To this end, the use of ATAC sequencing of human circulating monocytes has been optimised. These findings lay the foundation from which to understand the transcriptional regulation of monocytes in breast cancer.
Supervisor: Pollard, Jeffrey ; Jenkins, Stephen Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: mouse model ; breast cancer ; MMTV-PyMT ; monocyte DNA ; monocyte production ; ATAC sequencing