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Title: Inflammation and colorectal cancer : elucidation of the cellular and molecular mechanisms by which interleukin 22 contributes to the development and progression of colorectal cancer
Author: McCuaig, Sarah
ISNI:       0000 0004 6501 0904
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2017
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Colorectal cancer (CRC) is a molecularly heterogeneous disease driven by the complex interplay between genetic factors, such as oncogenic mutations, and microenvironmental factors, such as aberrant immunity. Notably, interleukin 22 (IL- 22), which plays a critical role in intestinal epithelial repair, promotes CRC progression in murine models of both colitis-associated and sporadic CRC. However, the phenotypes associated with IL-22/IL-22 receptor expression in human CRC remain uncharacterized and the molecular mechanisms of IL-22-dependent tumourigenesis are not understood. Thus the primary aim of this study was to understand the mechanisms by which IL-22 contributes to the development and progression of human colorectal cancer. Specific driving mutations in human CRC critically influence the impact of the IL-22 pathway on disease progression. The KRAS oncogene is mutated in roughly 40% of colorectal cancers and carries a minor adverse prognostic impact. However, using independent training and validation cohorts in tumour transcriptomic datasets totalling 1820 patients, we identified that in patients with high tumoural expression of either or both subunits of the heterodimeric IL-22 receptor (IL22RA1, IL10RB), KRAS mutation markedly worsens prognosis. Using a panel of CRC cell lines and primary human organoids, we confirmed that this prognostic association is due to a functional interaction between IL-22 and mutant KRAS by observing that IL-22 enhances chemoresistance, 3-dimensional clonogenicity, and proliferation specifically in CRC cells with both high IL-22 receptor levels and KRAS mutations. Taking unbiased RNA-sequencing and proteomic approaches, we identified non-cell autonomous and cell autonomous pathways by which IL-22 may interact with KRAS to promote malignancy. IL-22 enhanced ELR+ CXC chemokine expression, which may condition a tumour-promoting immune microenvironment, and induced the Myc pathway, which may augment proliferation and glycolytic flux, in KRAS mutant cells. Collectively, this work has revealed that an IL-22 signal is interpreted differently in the presence or absence of mutant KRAS. Our data points toward a method to identify a subset of poor prognosis IL-22 receptor-high, KRAS mutant CRC patients and we hypothesise that blockade of the IL-22 pathway in these patients may have therapeutic benefit.
Supervisor: Powrie, Fiona Sponsor: Rhodes Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available