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

Bon Kyoung Koo, Johan H. Van Es, Maaike Van Den Born, Hans Clevers

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

130 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)7548-7550
Aantal pagina's3
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Volume112
Nummer van het tijdschrift24
DOI's
StatusGepubliceerd - 16 jun. 2015
Extern gepubliceerdJa

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