Research sheds new mild on p53 tumor suppressor gene’s position in ulcerative colitis

Researchers within the lab of Michael Sigal on the Max Delbrück Heart and Charité – Universitätsmedizin Berlin have elucidated the position of the p53 gene in ulcerative colitis. The examine, revealed in Science Advances, suggests a possible new drug goal to cease illness development to most cancers. 

A group of researchers led by Kimberly Hartl, a graduate scholar on the Berlin Institute for Medical Programs Biology of the Max Delbrück Heart (MDC-BIMSB) and Charité – Universitätsmedizin, have shed new mild on the position of the p53 tumor suppressor gene within the pathogenesis of ulcerative colitis (UC) – an inflammatory bowel illness that afflicts an estimated 5 million folks worldwide and that’s linked to an elevated threat of colon most cancers. The analysis factors to a brand new method to cease the illness from progressing. The examine was revealed within the journal Science Advances.

In sufferers with ulcerative colitis who’re at excessive threat for creating most cancers, we might doubtlessly goal aberrant cells and do away with them early, earlier than any most cancers happens.”

Professor Michael Sigal, Group Chief of the Gastrointestinal Barrier, Regeneration Carcinogenesis lab at MDC-BIMSB, Head of Luminal Gastroenterology at Charité, and senior creator of the paper

A key position for p53

Ulcerative colitis impacts the massive gut, particularly areas referred to as “crypts,” tube-like glands throughout the epithelial tissue that traces the gut. Crypts comprise stem cells and different cell varieties that preserve the well being and regular operate of the colon, equivalent to absorbing vitamins or secreting mucus. 

When the colon is injured, epithelial crypt cells enter a “restore mode.” They start to proliferate quickly to repair the damage. Nevertheless, in sufferers with UC and UC-related colon cancers, these cells turn into caught in restore mode, which scientists confer with as a “regenerative cell state.” In consequence, there are too few mature cells. Consequently, the colon struggles to operate usually, which triggers much more stem cell proliferation in a poisonous suggestions loop.

Within the present examine, Hartl discovered this faulty restore mechanism is linked to a non-functional p53 gene, which performs a key position in regulating the cell cycle and in repairing DNA. 

 “If there is no such thing as a p53, cells stay in a proliferative state,” Sigal explains.

Present exams to seek out precancerous lesions in sufferers with UC equivalent to colonoscopies can establish seen lesions that typically are usually not straightforward to take away, says Sigal. This examine may very well be a primary step in creating molecular instruments for a much less invasive diagnostic check that might permit physicians to establish the aberrant cells a lot earlier, even earlier than seen alterations happen, he provides. 

Regeneration gone hay-wire 

To check the restore course of, the researchers developed a three-dimensional organoid – a mini organ – mannequin of the colon grown from mouse stem cells. 

Along with specialists in DNA and RNA sequencing in addition to proteomics and metabolomic know-how on the Max Delbrück Heart, they discovered that cells in organoids missing p53 are caught within the regenerative state. Thus, the cells metabolize glucose extra quickly by way of the method of glycolysis. In contrast, when p53 is lively, it diminishes glucose metabolism and alerts cells to re-enter a wholesome state.

The scientists then handled the organoids with compounds that intrude with glycolysis to check whether or not they can goal these extremely proliferative cells. They discovered that cells that lacked the p53 gene had been extra weak to this therapy than regular cells. “With organoids, we are able to establish very particular brokers that may goal metabolic pathways and level us towards doubtlessly new therapeutics to selectively goal mutated cells,” Hartl provides. 

The following step is to switch these findings to the human setting. The researchers are additionally now finding out the restore course of in additional element with the objective of creating extra easy strategies to establish cells with faulty p53 genes in colon tissue.

“As soon as we’ve a easy technique of figuring out these particular person cells in colon tissues, we might carry out scientific research to selectively kill them, after which analyze whether or not that is related to a decrease threat of creating most cancers,” says Sigal.