| Summary: | <p>Colorectal cancer (CRC) is a heterogenous disease of the intestinal epithelium that is characterised by the accumulation of mutations and a dysregulated immune response. A growing body of literature now also illustrates that this is accompanied by an “oncogenic” CRC-associated microbiota, but whether this dysbiosis is a functional hallmark of CRC or merely a bystander effect of disease is unclear. Therefore, the aim of this DPhil project was to identify changes within the microbiome during cancer progression and the functional consequences. To achieve this, we induced dysbiosis in genetically susceptible mice by colonisation with the pathobiont Helicobacter hepaticus (Hh) followed by the treatment with the carcinogen azoxymethane (HhAOM).</p>
<p>Using a range of unbiased longitudinal approaches, we found a distal colon-specific neutrophil signature during tumorigenesis and identified 118 genes that were differentially expressed in HhAOM versus control mice, indicative of putative tumour-promoting properties. Amongst these, the enzyme peptidyl arginine deaminase 4 (PAD4) was upregulated in epithelial cells of early and late tumorigenesis. PAD4 was verified to play a functional role in cancer progression because therapeutic in vivo inhibition reduced tumour area. Alongside this observation, we discovered that Hh resides within established tumours but lacks the capability to drive CAC in gnotobiotic settings.</p>
<p>Collectively, our findings suggest that Hh-driven colitis triggers an early neutrophil influx into the distal colon which fosters a microenvironment that promotes tumour progression characterised by the expression of PAD4. These observations open new potential avenues to explore tumour-promoting function of neutrophil subsets in more detail and the role of the citrullination enzymes like PAD4 in CRC progression.</p>
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