R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine
Metadatos
Mostrar el registro completo del ítemAutor
Han, Teng; Schatoff, Emma M; Murphy, Charles; Zafra, Maria Paz; Wilkinson, John E.; Elemento, Olivier; Dow, Lukas EEditorial
Nature
Materia
R-Spondin chromosome rearrangements Colorectal cancer WNT CRISPR-Cas9
Fecha
2017Referencia bibliográfica
Han T, Schatoff EM, Murphy C, Zafra MP, Wilkinson JE, Elemento O, Dow LE. R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine. Nat Commun. 2017 Jul 11;8:15945.
Patrocinador
DNA FISH analysis was performed by the Memorial Sloan Kettering Cancer Center (MSKCC) Molecular Cytogenetics Core, with support from an NIH Cancer Center support grant (P30 CA008748). This work was supported by a pilot grant from the Center for Advanced Digestive Care (CADC) at Weill Cornell Medicine, and a project grant from the NIH/NCI (CA195787-01) and a project grant from the Starr Cancer Consortium (I10-0095). E.M.S. was supported by a Medical Scientist Training Program grant from the National Institute of General Medical Sciences of the National Institutes of Health under Award Number T32GM07739 to the Weill Cornell/Rockefeller/Sloan-Kettering Tri-Institutional MD-PhD Program. L.E.D. was supported by a K22 Career Development Award from the NCI/NIH (CA 181280-01).Resumen
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.