Chalmers Conferences, 9th European Conference on Mathematical and Theoretical Biology

Clonal evolution of human intestinal stem cell niches
Marnix Jansen

Last modified: 2014-06-09


Cancer is a genetic disease that develops over many years, providing a ‘window of opportunity’ for early treatment. Tumor growth is initiated by mutations in tissue-specific stem cells, which initiate a process of Darwinian clonal competition, selection and expansion. The mouse intestinal crypt has become a favored model system for investigating patterns of stem cell competition and the effect of pathogenic (K-Ras, APC, p53, and so on) mutations. These techniques however depend on the transgenic introduction of lineage markers, something not feasible in cancer patients. Alternatively,
non-pathogenic naturally-occurring mutations that occur due to background mutation can be used as neutral lineage markers in patient material. We have developed a novel system to trace the clonal output of a single stem cell lineage within stem cell niches in the human large bowel. We find that crypts in the large bowel contain multiple stem cells, which compete for space within the niche. Individual lineages undergo drift consistent with neutral competition. We have also applied this technique to crypts harvested from patients afflicted by Familial Adenomatous Polyposis (FAP). These patients are at increased risk of developing colorectal cancer due to a germline APC mutation, which leads to the development of numerous dysplastic colorectal cancer precursor stages. Some of these dysplastic precursor lesions inevitably progress to cancer. We have compared stem cell behavior in normal-appearing crypts and dysplastic crypts from these FAP patients and compared these patterns to normal controls. Chemopreventive drugs may tip the balance to favor the clearance of mutated stem cells in intestinal stem cell niches.