Different in vivo and in vitro transformation of intestinal stem cells in mismatch repair deficiency

摘要: Mutations in mismatch repair (MMR) genes result microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence frequency intestinal stem cell (ISC) transformation, we quantified MSI growth characteristics organoids Msh2-deficient control mice from birth until tumor formation related them to tissue gene expression. Although continuously increased birth, remained stable at first. Months before onset, normal contained precursor cells forming with higher MSI, cystic rates resembling temporarily those organoids. Consistently, exhibited a tumor-like signature. Normal showed inheritable transient cyst-like growth, which became independent R-spondin. ISC transformation proceeded faster vitro than vivo underlying genotype but more under MMR deficiency. Transient not was suppressed by aspirin. In summary, as highlighted organoids, molecular alterations long MMR-deficient intestine, thus increasing its susceptibility for transformation.