title: Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia.
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.
authors.affiliation: 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.
authors.forename: Bon-Kyoung
authors.initials: BK
authors.lastname: Koo
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: van den Born
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D000217:Acyltransferases; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000172:deficiency / Q000235:genetics; D044482:Benzeneacetamides / Q000494:pharmacology*; D006801:Humans; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D019899:Paracrine Communication / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060508:Wnt3 Protein / Q000172:deficiency / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D000217:Acyltransferases; D051792:Basic Helix-Loop-Helix Proteins; D044482:Benzeneacetamides; D008565:Membrane Proteins; D011725:Pyridines; D044767:Ubiquitin-Protein Ligases; D060508:Wnt3 Protein; C579131:2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide; C500943:Atoh1 protein, mouse; C555508:Wnt3 protein, mouse; C491187:Porcn protein, mouse; C575493:RNF43 protein, mouse; C572951:Znrf3 protein, mouse
keywords: LGR5; RNF43; Wnt; ZNRF3; porcupine inhibitor