Researchers have clarified how the p53 gene functions in ulcerative colitis, revealing a possible new target for drugs aimed at preventing the disease from progressing to cancer.
Researchers from the lab of Michael Sigal at the Max Delbrück Center and Charité — Universitätsmedizin Berlin have clarified the function of the p53 gene in ulcerative colitis. Their study, published in Science Advances, indicates a promising new drug target that could help halt the progression of the disease to cancer.
A research team 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, has provided new insights into how the p53 tumor suppressor gene contributes to the development of ulcerative colitis (UC) – an inflammatory bowel condition that affects approximately five million individuals globally and is associated with a heightened risk of colon cancer. This research points to a novel approach to deter the advancement of the disease. The findings were shared in the journal Science Advances.
“In patients with ulcerative colitis who have a high risk of developing cancer, we could aim to eliminate dysfunctional cells early, potentially preventing any cancer from forming,” states Professor Michael Sigal, who leads the Gastrointestinal Barrier, Regeneration Carcinogenesis lab at MDC-BIMSB and is Head of Luminal Gastroenterology at Charité, as well as a senior author of the study.
The Importance of p53
Ulcerative colitis impacts the large intestine, particularly areas known as “crypts,” which are tubular glands located within the epithelial tissue lining the intestine. These crypts contain stem cells and various other cell types that play essential roles in maintaining the colon’s health and functionality, such as nutrient absorption and mucus secretion.
When the colon sustains injury, the epithelial crypt cells activate a “repair mode,” leading them to proliferate rapidly to address the damage. However, in patients suffering from UC and its associated colon cancers, these cells can get trapped in this repair state, known as a “regenerative cell state.” This situation results in an insufficient number of mature cells, and the colon struggles to operate normally, which perpetuates excessive stem cell proliferation in a harmful feedback loop.
In this study, Hartl discovered that this faulty repair mechanism is associated with a non-functional p53 gene, which is crucial for overseeing the cell cycle and aiding in DNA repair.
“When p53 is absent, cells stay in a state of constant proliferation,” explains Sigal.
Current diagnostic techniques, such as colonoscopies, can help detect precancerous lesions in UC patients, although they might only identify visible lesions that are difficult to remove, according to Sigal. This study might represent a foundational step toward creating molecular tools for a less invasive diagnostic test, enabling doctors to locate these abnormal cells much sooner, even before any visible changes are present, he adds.
Disordered Regeneration
To investigate the repair process, the researchers created a three-dimensional organoid – a miniature organ – model of the colon derived from mouse stem cells.
Collaborating with experts in DNA and RNA sequencing, as well as proteomics and metabolomics at the Max Delbrück Center, they discovered that p53-deficient cells within organoids remain trapped in a regenerative state. This leads to accelerated glucose metabolism through glycolysis. Conversely, when p53 is functioning, it reduces glucose metabolism and encourages cells to transition back into a healthy state.
The researchers subsequently treated the organoids with agents that disrupt glycolysis to determine if these compounds could effectively target the rapidly dividing cells. They observed that cells lacking the p53 gene exhibited greater susceptibility to this treatment than normal cells. “Using organoids, we can pinpoint specific agents that can disrupt metabolic pathways and guide us toward potentially new therapeutic strategies designed to selectively target mutated cells,” adds Hartl.
The next step involves applying these insights to human cases. The team is also delving deeper into the repair mechanism with the aim of developing simpler methods to detect cells with dysfunctional p53 genes in colon tissue.
“Once we establish an easy approach to identify these specific cells in colon tissues, we could conduct clinical trials to selectively eliminate them and subsequently assess whether this correlates with a reduced risk of developing cancer,” Sigal concludes.
