Frizzled-7 is required for Wnt signaling in gastric tumours with and without Apc mutations

Flanagan, Dustin J., Barker, Nick, Di Costanzo, Natasha S., Mason, Elizabeth A., Gurney, Austin, Meniel, Valerie S., Koushyar, Sarah, Austin, Chloe R., Ernst, Matthias, Pearson, Helen B. ORCID: https://orcid.org/0000-0002-3284-0843, Boussioutas, Alex, Clevers, Hans, Phesse, Toby J. ORCID: https://orcid.org/0000-0001-9568-4916 and Vincan, Elizabeth 2019. Frizzled-7 is required for Wnt signaling in gastric tumours with and without Apc mutations. Cancer Research 79 (5) , pp. 970-981. 10.1158/0008-5472.CAN-18-2095

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Abstract

A subset of patients with gastric cancer have mutations in genes that participate in or regulate Wnt signaling at the level of ligand (Wnt) receptor (Fzd) binding. Moreover, increased Fzd expression is associated with poor clinical outcome. Despite these findings, there are no in vivo studies investigating the potential of targeting Wnt receptors for treating gastric cancer, and the specific Wnt receptor transmitting oncogenic Wnt signaling in gastric cancer is unknown. Here, we use inhibitors of Wnt/Fzd (OMP-18R5/vantictumab) and conditional gene deletion to test the therapeutic potential of targeting Wnt signaling in preclinical models of intestinal-type gastric cancer and ex vivo organoid cultures. Pharmacologic targeting of Fzd inhibited the growth of gastric adenomas in vivo. We identified Fzd7 to be the predominant Wnt receptor responsible for transmitting Wnt signaling in human gastric cancer cells and mouse models of gastric cancer, whereby Fzd7-deficient cells were retained in gastric adenomas but were unable to respond to Wnt signals and consequently failed to proliferate. Genetic deletion of Fzd7 or treatment with vantictumab was sufficient to inhibit the growth of gastric adenomas with or without mutations to Apc. Vantictumab is currently in phase Ib clinical trials for advanced pancreatic, lung, and breast cancer. Our data extend the scope of patients that may benefit from this therapeutic approach as we demonstrate that this drug will be effective in treating patients with gastric cancer regardless of APC mutation status.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences European Cancer Stem Cell Research Institute (ECSCRI)
Publisher:	American Association for Cancer Research
ISSN:	0008-5472
Date of First Compliant Deposit:	20 December 2018
Date of Acceptance:	4 January 2019
Last Modified:	06 Nov 2023 21:39
URI:	https://orca.cardiff.ac.uk/id/eprint/117844

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