Two-stage genome-wide 5-hydroxymethylcytosine (5hmC) reprogramming during colorectal carcinogenesis and liver metastasis

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This research is designed to investigate the role 5hmC plays in colon cancer. We already know that levels of 5hmC are much higher in normal colon cells than colon cancer cells, and previous research into other cancers has shown that stimulating cells to produce more 5hmC leads to slower tumour growth. 5hmC is therefore seen as a potential diagnostic biomarker for many cancers. However, not all cancers behave identically and there is still very little understanding of how the loss of 5hmC actually contributes to colon cancer. Our goal is to determine whether targeting 5hmC is a viable therapeutic option for treating colon cancer specifically.We have two research objectives:1. To discover what role 5hmC plays during colon cancer progression2. To discover how changes in 5hmC levels affect metastasisFor the first objective we will investigate two specific models for 5hmC function. The first addresses whether reduced levels of 5hmC affect the way RNA is created ("spliced"). There is evidence that when present near the splice sites, 5hmC facilitates successful splicing and it is therefore logical to hypothesise that when 5hmC is removed splicing may occur aberrantly. Several cancers have a population of aberrantly spliced RNA variants that can drive cancer cells and enable them to divide continually and become invasive. The second model is based on findings that have shown that the production of 5hmC is necessary for normal colon cell development. The colon is lined with a series of finger-like projections called villi, at the base of which there is a pool of colon stem cells capable of developing into mature colon cells. These stem cells have very little 5hmC and acquire 5hmC when they develop into the cells that form the mature villi. Colon cancer cells have many similar features to colon stem cells including a lack of 5hmC. Therefore we are testing whether the lack of 5hmC helps cancer cells to remain stem-like and continually divide.For the second objective we have evidence that 5hmC levels might actually increase when colon cancer cells spread ("metastasise") to the liver. During metastasis cells change their shape in order to migrate to different sites. This shape-changing process is the same process that occurs during embryonic development when cells migrate to different regions in order to form various organs. The enzymes involved in producing 5hmC play a prominent role during this developmental process. We will therefore test whether tumour cells that have been treated to produce more 5hmC have an increased or decreased ability to form metastatic tumours. We will also do the complementary analysis to see whether cancer cells with an inability to produce 5hmC can become more or less invasive. The outcome of this research will help us understand how this epigenetic mark works and also tell us whether targeting 5hmC levels in colon cancer is a safe therapeutic option from which patients would be likely to benefit.