In a groundbreaking study, researchers at the Max Delbrück Center and Charité – Universitätsmedizin Berlin uncover the crucial role of the p53 tumor suppressor gene in ulcerative colitis, offering hope for new treatments to prevent progression to colon cancer.
A significant breakthrough in understanding the link between ulcerative colitis (UC) and cancer has been made by researchers at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB) and Charité – Universitätsmedizin Berlin. The team, led by graduate student Kimberly Hartl, has discovered that a dysfunctional p53 gene plays a pivotal role in the pathogenesis of UC, promising new avenues for treatment to halt the progression to cancer.
Published in Science Advances, the study delves into how the p53 gene — a crucial tumor suppressor — fails to regulate the cell cycle and DNA repair in UC patients, thereby increasing their cancer risk.
Uncovering the Mechanism
Ulcerative colitis, which affects around 5 million people worldwide, primarily damages the large intestine, specifically the crypts — tube-like glands in the epithelial tissue. These crypts house stem cells that are essential for the colon’s health and proper function.
When the colon sustains injury, these epithelial crypt cells enter a repair mode, proliferating rapidly to mend the damage. However, in individuals with UC, this process goes awry, trapping cells in a regenerative state and leading to impaired colon function.
The study sheds light on the p53 gene’s critical role in this mechanism. The colon’s struggle to function normally in UC triggers a toxic feedback loop of excessive stem cell proliferation.
“If there is no p53, cells remain in a proliferative state,” senior author Michael Sigal, a group leader of the Gastrointestinal Barrier, Regeneration Carcinogenesis lab at MDC-BIMSB and head of Luminal Gastroenterology at Charité, said in a news release.
Towards New Diagnostics and Treatments
Current methods like colonoscopies can spot visible lesions but might miss early, non-visible abnormalities. The findings raise the possibility of developing molecular diagnostic tools to detect and eliminate aberrant cells before cancer develops.
“In 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,” Sigal added.
In their study, the team used three-dimensional organoid models of the colon derived from mouse stem cells. These models enabled them to observe that cells lacking functional p53 were stuck in the regenerative state, leading to increased glucose metabolism through glycolysis.
The researchers experimented with glycolysis inhibitors, discovering that p53-deficient cells were more susceptible to these treatments, opening doors to targeted therapeutic interventions.
“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,” Hartl said in the news release.
Next Steps
Moving forward, the team plans to apply these findings to human studies. They aim to develop simpler methods to identify cells with defective p53 genes in colon tissue, potentially leading to clinical studies to selectively eliminate these cells and mitigate cancer risk.
“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,” Sigal added.
The implications of this study extend beyond merely understanding UC; they offer a beacon of hope for devising preventive strategies against colon cancer in at-risk populations.