Driver mutations of the adenoma-carcinoma sequence govern the intestinal epithelial global translational capacity.

In colorectal cancer, the role of the most common driver mutations in APC, KRAS, SMAD4 and TP53, on global mRNA translation are incompletely understood. To adress this, we generated and characterised mouse intestinal organoid models with oncogenic mutations in each of these genes using Cre-Lox recombination in ex vivo organoid cultures combined with stable expression of short hairpin RNAs. Microarray analysis was used to characterise transcriptomic reprogramming that supports altered global translation rates in mutant cells. Using genetically modified organoid models we compared intestinal epithelial cells with the following genotypes: 1) wildtype 2) Apc loss 3) Apc loss and oncogenic KrasG12D 4) Apc loss, oncogenic KrasG12D and Smad4 loss 4) Apc loss, oncogenic KrasG12D, Smad4 loss and p53 loss.