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Nat Commun. 2017 Jul 11;8:15945. doi: 10.1038/ncomms15945.

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

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Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA.
Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, New York 10021, USA.
Weill Cornell/Rockefeller/Sloan Kettering Tri-I MD-PhD Program, New York, New York 10021, USA.
The Tri-Institutional Training Program in Computational Biology and Medicine, New York, New York 10021, USA.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
Department of Biochemistry, Weill Cornell Medicine, New York, New York 10021, USA.


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.

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