Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Jun 16;112(24):7548-50. doi: 10.1073/pnas.1508113112. Epub 2015 May 28.

Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia.

Author information

1
Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands h.clevers@hubrecht.eu bkk25@cam.ac.uk.
2
Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.

Abstract

Rnf43 (RING finger protein 43) and Znrf3 (zinc/RING finger protein 3) (RZ) are two closely related transmembrane E3 ligases, encoded by Wnt target genes, that remove surface Wnt (wingless-int) receptors. The two genes are mutated in various human cancers. Such tumors are predicted to be hypersensitive to, yet still depend on, secreted Wnts. We previously showed that mutation of RZ in the intestine yields rapidly growing adenomas containing LGR5(+) (leucine-rich repeat-containing G-protein coupled receptor 5) stem cells and Wnt3-producing Paneth cells. We now show that removal of Paneth cells by Math1 mutation inhibits RZ(-/-) tumor formation. Similarly, deletion of Wnt3 inhibits tumorigenesis. Treatment of mice carrying RZ(-/-) intestinal neoplasia with a small molecule Wnt secretion inhibitor (porcupine inhibitor C59) strongly inhibited growth, whereas adjacent normal crypts remained intact. These results establish that paracrine Wnt secretion is an essential driver of RZ(-/-) tumor growth and imply that a therapeutic window exists for the use of porcupine inhibitors for RZ-mutant cancers.

KEYWORDS:

LGR5; RNF43; Wnt; ZNRF3; porcupine inhibitor

PMID:
26023187
PMCID:
PMC4475934
DOI:
10.1073/pnas.1508113112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center