Researchers at the Max Delbrück Center and Charité — Universitätsmedizin Berlin have conducted a study on the role of the p53 gene in ulcerative colitis (UC). This inflammatory bowel disease is linked to an increased risk of colon cancer, affecting millions worldwide. The study, published in Science Advances, suggests a potential new drug target to prevent disease progression to cancer. The research aims to identify aberrant cells in patients with UC who are at high risk for developing cancer and eliminate them before cancer occurs.
The study, led by Kimberly Hartl, a graduate student at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center and Charité, sheds light on the role of the p53 tumor suppressor gene in the pathogenesis of UC. Professor Michael Sigal, the Group Leader of the Gastrointestinal Barrier, Regeneration Carcinogenesis lab at MDC-BIMSB, highlights the potential to target aberrant cells in patients with UC to prevent cancer development. By understanding the defective repair mechanism linked to a non-functional p53 gene, the researchers aim to stop the toxic feedback loop that triggers stem cell proliferation in UC patients.
In patients with UC, the large intestine is affected, particularly the crypts, tube-like glands within the epithelial tissue lining the intestine. These crypts contain stem cells and other cell types that maintain normal colon function. However, in patients with UC and UC-related colon cancers, these cells become stuck in a regenerative state, with too few mature cells present. The study shows that this defective repair mechanism is linked to a non-functional p53 gene, crucial for regulating the cell cycle and repairing DNA. Without p53, cells remain in a proliferative state, contributing to the progression of disease.
To study the repair process, the researchers developed a three-dimensional organoid model of the colon grown from mouse stem cells. They found that cells lacking p53 are stuck in a regenerative state and metabolize glucose more rapidly through glycolysis. By contrast, active p53 diminishes glucose metabolism, signaling cells to return to a healthy state. Testing compounds that interfere with glycolysis on the organoids showed that cells lacking p53 were more vulnerable to this treatment. This suggests potential new therapeutics to selectively target mutated cells in UC patients.
The researchers aim to transfer these findings to the human setting and further study the repair process to develop simple methods for identifying cells with defective p53 genes in colon tissue. By developing a less invasive diagnostic test, physicians could identify aberrant cells early, even before visible alterations occur. Clinical studies to selectively target and kill these cells in colon tissues could then be performed to analyze the impact on cancer risk. The research could lead to advancements in personalized medicine for patients with UC at risk for developing cancer, offering new opportunities for early intervention and prevention.
