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

TitleR-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine.
Publication TypeJournal Article
Year of Publication2017
AuthorsHan T, Schatoff EM, Murphy C, Zafra MPaz, Wilkinson JE, Elemento O, Dow LE
JournalNat Commun
Date Published2017 07 11
KeywordsAcyltransferases, Animals, Chromosome Aberrations, Chromosomes, Colonic Neoplasms, Female, Gene Rearrangement, Humans, Intestines, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Pyrazines, Pyridines, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Thrombospondins, Wnt Proteins

Defining the genetic drivers of cancer progression is a key in 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 tumour development in vivo, without additional cooperating genetic events. Rspo-fusion tumours are entirely Wnt-dependent, as treatment with an inhibitor of Wnt secretion, LGK974, drives rapid tumour clearance from the intestinal mucosa without effects on normal intestinal crypts. Altogether, our study provides direct evidence that endogenous Rspo2 and Rspo3 chromosome rearrangements can initiate and maintain tumour development, and indicate a viable therapeutic window for LGK974 treatment of RSPO-fusion cancers.

Alternate JournalNat Commun
PubMed ID28695896
PubMed Central IDPMC5508203
Grant ListK22 CA181280 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA195787 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States