Here, we describe the first application of transgenic and inducible CRISPR/Cas9 technology to investigate cancer-associated chromosome rearrangements in vivo, and show that endogenous PTPRK–RSPO3 and EIF3E–RSPO2 rearrangements are sufficient to initiate hyperproliferation and tumour development in the intestine. Here, RSPO3 is linked to cancer.