R-Spondin chromosome rearrangements drive Wnt-dependent tumor initiation and maintenance in the intestine

Defining the genetic drivers of cancer progression is key to understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo. We show that both Rspo2 and Rspo3 fusion events are sufficient to initiate hyperplasia and tumor development in vivo, without additional cooperating genetic events. Rspo fusion tumors are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumor clearance from the intestinal mucosa without effects on normal intestinal crypts. Together, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumor development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers. Overall design: Examination of transcriptional changes associated with RSPO2 and RSPO3 gene fusions in intestinal organoid model.