WP4: Model systems to study the colorectal cancer microbiome

The Clevers lab has been using their human ‘mini-gut’ technology. These mini guts (a.k.a. intestinal organoids) are grown in a dish from healthy gut stem cells. They can be expanded indefinitely and create miniature versions of the human gut. It has turned out that it is possible to chronically expose these mini-guts to potentially carcinogenic bacteria by weekly injections of these bacteria into the interior of the mini-guts. 

 Several bacterial species that are frequently found in the human intestines are suspected to contribute to the occurrence of colon cancer. One of these is a special strain (“pks”) of the best-known gut bug, E coli. In a collaboration with several other members of the consortium, it was shown that pks E coli induces unique and easily recognizable changes (‘mutations’) in the DNA of the human mini-gut cells. The same mutational signature was subsequently found to be present in the DNA of a significant fraction of human colon cancers. This ‘smoking gun’ implies that pks E coli is involved in the occurrence of a subset of human colon cancers  

 The Garrett Lab studies intestinal microbes and how their metabolites affect the development of bowel cancer. Short-chain fatty acids are metabolites generated by intestinal microbes from dietary fiber. In a recent publication, the Garrett Lab investigated the mechanisms by which free fatty acid receptor 2 (FFAR2), a receptor for short-chain fatty acids expressed by cancer cells and immune cells within the tumor microenvironment, afford protection from the development and progression of bowel cancer.

Work Package Leaders