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

Teng Han, Emma M. Schatoff, Charles Murphy, Maria Paz Zafra, John E. Wilkinson, Olivier Elemento and Lukas E. Dow ()
Additional contact information
Teng Han: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Emma M. Schatoff: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Charles Murphy: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Maria Paz Zafra: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
John E. Wilkinson: University of Michigan School of Medicine
Olivier Elemento: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine
Lukas E. Dow: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/ncomms15945 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15945

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms15945

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().