Date: October 30, 2024
Source: Max Delbrück Center and Charité—Universitätsmedizin Berlin

Summary:
Research from the lab of Dr. Michael Sigal at the Max Delbrück Center and Charité—Universitätsmedizin Berlin has uncovered a significant link between the p53 tumor suppressor gene and ulcerative colitis (UC), a chronic inflammatory bowel disease affecting millions worldwide and increasing the risk of colon cancer. The findings, published in Science Advances, could lead to new diagnostic and therapeutic approaches targeting the early stages of UC-related cancer development.

Researchers investigated p53’s role using 3D organoid models and mouse studies. They discovered that a faulty p53 gene hinders the regenerative process within the colon, keeping cells in a constant, unhealthy repair mode, which may drive UC-linked cancer progression. “In high-risk UC patients, we could potentially target aberrant cells early, before cancer occurs,” stated Dr. Sigal, Group Leader of the Gastrointestinal Barrier, Regeneration, and Carcinogenesis Lab at MDC-BIMSB.

Revealing the Repair Process

UC primarily affects “crypts” in the large intestine—glandular structures that house stem cells vital to colon health. In healthy tissue, these cells regenerate and differentiate in response to injury, but in UC patients, chronic inflammation traps cells in a “regenerative state,” leading to abnormal proliferation and impairing colon function. This dysfunctional repair cycle is closely tied to non-functional p53 genes, a well-known regulator of cell growth and DNA repair.

The team created mini-organ models, or organoids, from mouse stem cells to examine this phenomenon further. They found that cells lacking p53 remain locked in a highly proliferative, energy-consuming state, fueled by glycolysis. “When p53 is absent, cells fail to reestablish normal function, becoming ‘stuck’ in a state that resembles the fetal epithelium,” the researchers wrote. In contrast, when p53 is active, it inhibits excessive glucose metabolism, signaling cells to re-enter a normal, healthy state.

Targeting Vulnerable Cells

Using specialized sequencing and proteomic tools, the team identified compounds that inhibit glycolysis and selectively target cells lacking p53, showing potential for drug therapies aimed at these aberrant cells. “With organoids, we can find specific agents that target metabolic pathways, potentially leading to new treatments that precisely target mutated cells,” said Kimberly Hartl, the study’s first author and a graduate student at the MDC-BIMSB.

Future Clinical Applications

The researchers aim to adapt these findings for human use, developing a simpler method to identify cells with defective p53 in colon tissue. Dr. Sigal noted, “If we can identify these cells early, we could test therapies to selectively eliminate them, potentially reducing cancer risk in UC patients.”

This study lays the groundwork for future clinical studies focused on early intervention and more personalized care for UC patients at elevated cancer risk.

Journal Reference:
Hartl, K., Sigal, M., et al. “p53 terminates the regenerative fetal-like state after colitis-associated injury.” Science Advances, 2024.