"The functioning of intestinal stem cells relies on growth factors, named Wnts, produced by the surrounding environment. Intestinal cancers typically originate from stem cells where mutations allow growth independent of these factors. When we removed a gene called Notum, which renders Wnts inactive, from mutated stem cells, the number of precancerous adenomas in the intestine was greatly reduced. We found that mutated cells use this gene to block environmental factors critical to normal stem cells gaining advantage in competition," says Postdoctoral Researcher Nalle Pentinmikko.
The research group of Assistant Professor Pekka Katajisto at the Institute of Biotechnology of the University of Helsinki had already previously discovered that the same gene, also called an 'ageing gene', is expressed in normal tissue when we age, reducing the ability of stem cells to repair damage. The current study shows that mutated cells use the same gene in order to establish a permanent footing in the tissue.
"Mutated cells kind of hijack the ageing gene and use it against the healthy stem cells," Katajisto says.
The results from this study may lead to the development of new therapies, because the function of the enzyme encoded by the ageing gene can be blocked pharmacologically. The research group led by Katajisto has previously used a compound for this purpose in aged research animals to enhance the function of aged stem cells. In the current study, researchers used the same method to reduce the chance of mutated cells winning in competition. A three-week treatment reduced the number of adenomas in animal models.
"The results are promising and create a foundation for developing new therapies for patients predisposed to intestinal cancers. This research demonstrates that by enhancing the natural mechanisms of how tissues remove damaged cells, we could also reduce cancer risk in other tissues," Pekka Katajisto concludes.
Flanagan DJ, Pentinmikko N, Luopajärvi K, Willis NJ, Gilroy K, Raven AP, Mcgarry L, Englund JI, Webb AT, Scharaw S, Nasreddin N, Hodder MC, Ridgway RA, Minnee E, Sphyris N, Gilchrist E, Najumudeen AK, Romagnolo B, Perret C, Williams AC, Clevers H, Nummela P, Lähde M, Alitalo K, Hietakangas V, Hedley A, Clark W, Nixon C, Kirschner K, Jones EY, Ristimäki A, Leedham SJ, Fish PV, Vincent JP, Katajisto P, Sansom OJ.
NOTUM from Apc-mutant cells biases clonal competition to initiate cancer.
Nature. 2021 Jun 2. doi: 10.1038/s41586-021-03525-z