Intestinal region-specific Wnt signalling profiles reveal interrelation between cell identity and oncogenic pathway activity in cancer development

We use a 3D in vitro organoid model to study the early phase of colorectal cancer development. In reaction to Wnt activation we observe downregulation of location specific genes and differentiation markers. Furthermore, the signature of Wnt target genes differs between organoids representing three locations of the murine intestine. The location specific Wnt signatures are dominated by genes which have been lowly expressed in the tissue of origin, and are the targets of transcription factors that are activated following enhanced Wnt signalling. We concude that the cell of origin has a substantial effect on the reaction to Wnt activation in a simple intestinal adenoma model. From three different murine intestinal locations we grow organoids. These are transformed to resemble adenomas after Wnt activation through lentiviral transduction with a stable form of beta-Catenin. The gene expression before and after Wnt activation is compared within each intestinal origin and across the three locations using RNA sequencing.