Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Pathology and Laboratory Medicine
Supervisor
Asfaha, Samuel
Abstract
Almost half of the human genome is comprised of transposable elements (TEs), that are endogenous viral elements in the DNA. In homeostasis, these elements are repressed by multiple mechanisms including epigenetic mechanisms such as DNA methylation and binding of the negative regulator tumor protein 53 (TP53). Interestingly, it was recently shown that re-expression of these elements inhibits tumor growth by activation of an interferon response also known as a viral mimicry response. The role that viral mimicry plays during colitis and cancer initiation, however, is not well understood. Here, we examined the role of viral mimicry on colitis-associated cancer initiation. Our findings demonstrate that re-expression of transposable elements and activation of a viral mimicry response (by inhibition of DNA methylation or p53 loss) inhibits colitis-associated cancer initiation. Importantly, loss of viral mimicry by knockout of the anti-viral signaling protein, mitochondrial antiviral-signaling protein (MAVS), reversed the antitumor effect of DNA hypomethylation and p53 loss and further promoted tumor formation. Furthermore, we found that activation of the viral mimicry response by DNA hypomethylation or p53 loss inhibits cancer initiation in a cell-autonomous manner with knockout of MAVS reversing this effect. Finally, we demonstrate that active colitis in both mice and patients is associated with activation of a viral mimicry response that is downregulated during early cancer development (i.e. dysplasia). These findings are consistent with viral mimicry playing a tumor suppressive role in colitis-associated tumorigenesis. Thus, our findings demonstrate that transposable elements and the viral mimicry response play an important role in colitis and colitis-associated cancer.
Summary for Lay Audience
Our genome contains many viral-like DNA sequences called transposable elements (TEs), which make up nearly half of our DNA. Normally, these elements are kept silent through various regulatory mechanisms that our cells possess. One way our cells can silence these viral elements and genes is through a DNA modification called DNA methylation. Another method is through the action of a protein called p53. Interestingly, recent studies have found that when these viral elements are re-activated, they can trigger an immune response that inhibits tumor growth, mimicking a viral infection. This effect is known as “viral mimicry”. In this research, we explored how this “viral mimicry” response influences the development of colorectal cancer associated with colitis, an inflammatory disease of the colon. We found that re-activating TEs—either by reducing DNA methylation or by loss of p53—suppresses the development of colitis-associated cancer. However, when a key “viral mimicry” protein called MAVS was no longer present, this protective effect was lost, resulting in colonic tumor formation. Furthermore, during colitis we detected activation of the viral mimicry response in both mice and humans. Upon progression to a pre-cancerous state, however, the viral mimicry response was lost, suggesting that the viral mimicry response is important role in preventing cancer formation. In summary, we show that expression of transposable elements with subsequent activation of a viral mimicry response are important for prevention of colitis-associated cancer.
Recommended Citation
Larsen, Frederikke, "The Role of Viral Mimicry in Colitis-Associated Cancer" (2025). Electronic Thesis and Dissertation Repository. 10807.
https://ir.lib.uwo.ca/etd/10807