2017
DOI: 10.1038/ncomms15945
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R-Spondin chromosome rearrangements drive Wnt-dependent tumour initiation and maintenance in the intestine

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 rearra… Show more

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Cited by 100 publications
(103 citation statements)
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References 43 publications
(62 reference statements)
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“…Interestingly, the EIF3E–RSPO2 fusion was reported to be sufficient to initiate WNT-dependent tumour development in a CRISPR-based murine colon cancer model, and the WNT secretion inhibitor LGK974 could drive rapid tumour clearance in this model 41. Thus, inhibition of WNT secretion (eg, using a porcupine inhibitor) might be a promising target for the treatment of hepatic RSPO2-activated tumours, and our molecular diagnostic approach might serve as companion diagnostic to select HCC patients that may benefit from such a precision medicine concept.…”
Section: Discussionmentioning
confidence: 99%
“…Interestingly, the EIF3E–RSPO2 fusion was reported to be sufficient to initiate WNT-dependent tumour development in a CRISPR-based murine colon cancer model, and the WNT secretion inhibitor LGK974 could drive rapid tumour clearance in this model 41. Thus, inhibition of WNT secretion (eg, using a porcupine inhibitor) might be a promising target for the treatment of hepatic RSPO2-activated tumours, and our molecular diagnostic approach might serve as companion diagnostic to select HCC patients that may benefit from such a precision medicine concept.…”
Section: Discussionmentioning
confidence: 99%
“…38 An in vivo study reported that LGK974 diminished/eradicated tumors carrying RSPO fusions from the intestinal mucosa without effects on normal intestinal crypts. 39 In addition, LGK974 prevented proliferation and induced differentiation of RNF43-mutant pancreatic adenocarcinoma in xenograft models. 40 Currently, a phase I clinical trial (Clinicaltrials.gov ID NCT01351103) of LGK974 for patients with malignancies of histological origin carrying genetic alterations upstream in the Wnt signaling pathway (eg, RNF43 mutation or RSPO fusion) is underway.…”
Section: P Orcupine Inhib Itor Smentioning
confidence: 98%
“…Another potent PORCN inhibitor, LGK974, was discovered by the screening of ~2 400 000 compounds using a TCF/LEF reporter assay, where Wnt3a‐secreting cells were cocultured with mouse Leydig TM3 cells expressing SuperTOPFlash for the activation of the Wnt pathway . An in vivo study reported that LGK974 diminished/eradicated tumors carrying RSPO fusions from the intestinal mucosa without effects on normal intestinal crypts . In addition, LGK974 prevented proliferation and induced differentiation of RNF43 ‐mutant pancreatic adenocarcinoma in xenograft models .…”
Section: Porcupine Inhibitorsmentioning
confidence: 99%
“…Finally, it will be interesting to evaluate LGRindependent, RSPO-mediated WNT signalling in cancer. Chromosomal abnormalities that lead to activation of RSPO2 or RSPO3 have been shown to drive WNT-dependent colon tumours 14 . Szenker-Ravi and colleagues' demonstration that these two RSPOs can modulate WNT activity independent of LGR adds a twist to these findings, and should prompt scientists to look for cancer-causing mutations in RSPO2 evolutionary model.…”
Section: Sizing Up Human Brain Evolutionmentioning
confidence: 99%