Viral mimicry acts as a tumor suppressor in colitis

Transposable elements (TEs) comprising nearly 50% of the genome are generally silenced by epigenetic mechanisms. Epigenetic anti-cancer drugs can lead to their re-expression, however, the role of TEs in tumorigenesis is unknown. Here, we demonstrate that TEs and their activation of a viral mimicry response plays an important tumor suppressive role in inflammation. We discovered that both patients and mice with colitis express TEs that lead to a viral mimicry response. Interestingly, this response inhibits stemness of cancer-initiating cells. Further activation of viral mimicry by DNA hypomethylation inhibits tumorigenesis. Conversely, knockout of the anti-viral signaling protein MAVS promotes tumorigenesis and reverses the anti-tumor effect of DNA hypomethylation, confirming a tumor suppressive role of viral mimicry. Consistent with this finding, patients with colitis-associated dysplasia show decreased expression of TEs and interferon-related genes. These findings suggest that activation of viral mimicry inhibits stemness and plays a key tumor suppressive role in inflammation. The role of normally silenced transposable elements (TEs) in tumorigenesis remains unclear. Here, the authors show that increased expression of TEs in both patients and mice with colitis or by DNA hypomethylating drugs elicits a viral mimicry response that suppresses tumorigenesis. This viral mimicry response inhibits the stemness of cancer initiating cells in a cell autonomous manner.