New Insights Into the Role of p53 in Intestinal Inflammation

A group of scientists from Charité – Universitätsmedizin and the Berlin Institute for Medical Systems Biology of the Max Delbrück Center have provided fresh insight into the pathophysiology of ulcerative colitis an inflammatory bowel disease that affects an estimated five million people globally and is associated with a higher risk of colon cancer.

The findings provide a novel approach to halting the disease's progression. The journal Science Advances published the study.

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.”

Michael Sigal, Professor and Study Senior Author, Max Delbrück Center

A Key Role for p53

Ulcerative colitis affects the large intestine, particularly the “crypts,” which are tube-like glands found in the intestinal lining's epithelial tissue. Stem cells and other cell types found in crypts support the colon's proper function and health, including mucus secretion and nutrition absorption.

When colon epithelial crypt cells sustain damage, they go into “repair mode” and start to multiply quickly to repair the damage. However, these cells become trapped in repair mode in individuals with UC and UC-related colon malignancies; doctors call this a “regenerative cell state.”

Consequently, the number of mature cells is insufficient. As a result, the colon finds it difficult to operate normally, which sets off a harmful feedback loop that further increases stem cell multiplication.

Hartl discovered in the current study that this flawed repair process is connected to a non-functioning p53 gene, which is essential for DNA repair and cell cycle regulation.

“If there is no p53, cells remain in a proliferative state,” Sigal explains.

Colonoscopies, one of the methods now used to detect precancerous lesions in UC patients, can detect visible lesions that are occasionally difficult to remove, according to Sigal. He adds that this discovery may be a first step in creating molecular tools for a less invasive diagnostic test that would enable doctors to spot the abnormal cells far sooner, even before changes become apparent.

Regeneration Gone Hay-Wire

The researchers created a three-dimensional organoid, or miniature organ, model of the colon using mouse stem cells to investigate the repair process.

They discovered that cells in organoids without p53 are trapped in the regenerative state, working with experts in DNA and RNA sequencing, proteomics, and metabolomic technology from the Max Delbrück Center. Thus, through the process of glycolysis, the cells metabolize glucose more quickly. On the other hand, p53 instructs cells to return to a healthy condition and reduces glucose metabolism when it is activated.

The researchers then administered substances that disrupt glycolysis to the organoids to see if they might target these highly proliferative cells. They discovered that p53-deficient cells were more susceptible to this therapy than normal cells.

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.”

Kimberly Hartl, Max Delbrück Center

Applying these discoveries to the human environment is the next stage. To create easier ways to detect cells in colon tissue that have faulty p53 genes, the researchers are now also looking more closely at the repair process.

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.”

Michael Sigal, Professor and Study Senior Author, Max Delbrück Center