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p53’s role in ulcerative colitis and its progression to cancer

Posted: 28 October 2024 | | No comments yet

The findings offer a promising drug target to prevent progression to colon cancer by targeting abnormal cells early on.

ulcerative colitis

The role of the p53 gene in the pathogenesis of ulcerative colitis (UC) has been revealed by researchers in the lab of Michael Sigal at the Max Delbrück Center and Charité – Universitätsmedizin. Their findings suggest a potential new drug target to prevent disease progression to cancer. 

Ulcerative colitis affects around five million people globally and is linked to an increased risk of colon cancer. Professor Michael Sigal, Group Leader of the Gastrointestinal Barrier, Regeneration Carcinogenesis lab at MDC-BIMSB, Head of Luminal Gastroenterology at Charité, and a senior author of the paper explained that aberrant cells could be targeted to eliminate them early, before cancer occurs in ulcerative colitis patients.

Regenerative cell state

UC specifically impacts areas named crypts, tube-like glands within the epithelial tissue that lines the intestine. Within crypts are stem cells and other cell types that maintain the health and normal function of the colon, like absorbing nutrients or secreting mucus. 

Epithelial crypt cells begin to proliferate quickly following an injury to the colon. 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. Therefore, there are too few mature cells so the colon struggles to function normally. This can initiate more stem cell proliferation in a toxic feedback loop.

The new study was 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. The team discovered that the defective repair mechanism is linked to a non-functional p53 gene, which has an essential role in regulating the cell cycle and in repairing DNA: if there is no p53, cells remain in a proliferative state.

Although current tests to find precancerous lesions in patients with UC such as colonoscopies can identify visible lesions that can be difficult to remove, the new findings could enable the development of molecular tools for a less invasive diagnostic test. This would allow physicians to identify aberrant cells much earlier, even before visible alterations happen.

Colon organoids

By using a colon organoid grown from mouse stem cells, the team worked with specialists in DNA and RNA sequencing as well as proteomics and metabolomic technology at the Max Delbrück Center. It was observed that cells in organoids lacking p53 are stuck in the regenerative state. This means that cells metabolise glucose more rapidly. Conversely, glucose metabolism is diminished and cells re-enter a healthy state when p53 is active.

Following this, the organoids were treated with compounds that interfere with glycolysis to assess whether they can target these highly proliferative cells. Cells that lacked the p53 gene were more vulnerable to this treatment than normal cells. Hartl stated: “With organoids, we can identify very specific agents that can target metabolic pathways and point us toward potentially new therapeutics to selectively target mutated cells.”

Now, these findings need to be translated into humans. Furthermore, the researchers are studying the repair process in more detail, aiming to develop 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 analyse whether this is associated with a lower risk of developing cancer,” concluded Sigal.

This study was published in Science Advances.