Abstract
The MSI2 RNA-binding protein is a potent oncogene playing key roles in haematopoietic stem cell homeostasis and malignant haematopoiesis. Here we demonstrate that MSI2 is expressed in the intestinal stem cell compartment, that its expression is elevated in colorectal adenocarcinomas, and that MSI2 loss-of-function abrogates colorectal cancer cell growth. MSI2 gain-of-function in the intestinal epithelium in a drug-inducible mouse model is sufficient to phenocopy many of the morphological and molecular consequences of acute loss of the APC tumour suppressor in the intestinal epithelium in a Wnt-independent manner. Transcriptome-wide RNA-binding analysis indicates that MSI2 acts as a pleiotropic inhibitor of known intestinal tumour suppressors including Lrig1, Bmpr1a, Cdkn1a and Pten. Finally, we demonstrate that inhibition of the PDK-AKT-mTORC1 axis rescues oncogenic consequences of MSI2 induction. Taken together, our findings identify MSI2 as a central component in an unappreciated oncogenic pathway promoting intestinal transformation.