Study sheds new light on p53 tumor suppressor gene's role in ulcerative colitis

A team of researchers led by Kimberly Hartl, a graduate student at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB) and Charité – Universitätsmedizin, have shed new light on the role of the p53 tumor suppressor gene in the pathogenesis of ulcerative colitis (UC) – an inflammatory bowel disease that afflicts an estimated five million people worldwide and that is linked to an increased risk of colon cancer. The research points to a new way to stop the disease from progressing. The study was published in the journal Science Advances.

Professor Michael Sigal, Group Leader of the Gastrointestinal Barrier, Regeneration Carcinogenesis lab at MDC-BIMSB, Head of Luminal Gastroenterology at Charité, and senior author of the paperIn patients with ulcerative colitis who are at high risk for developing cancer, we could potentially target aberrant cells and get rid of them early, before any cancer occurs."

A key role for p53

When the colon is injured, epithelial crypt cells enter a "repair mode." They begin to proliferate rapidly to fix the injury. However, in patients with UC and UC-related colon cancers, these cells become stuck in repair mode, which scientists refer to as a "regenerative cell state." As a result, there are too few mature cells. Consequently, the colon struggles to function normally, which triggers even more stem cell proliferation in a toxic feedback loop.

Regeneration gone hay-wire 

Together with specialists in DNA and RNA sequencing as well as proteomics and metabolomic technology at the Max Delbrück Center, they found that cells in organoids lacking p53 are stuck in the regenerative state. Thus, the cells metabolize glucose more rapidly via the process of glycolysis. By contrast, when p53 is active, it diminishes glucose metabolism and signals cells to re-enter a healthy state.

The next step is to transfer these findings to the human setting. The researchers are also now studying the repair process in more detail with the goal of developing more simple methods to identify cells with defective p53 genes in colon tissue.

"Once we have a simple method of identifying these individual cells in colon tissues, we could perform clinical studies to selectively kill them, and then analyze whether this is associated with a lower risk of developing cancer," says Sigal.

Source:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

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