Frizzled-7 is required for Wnt signaling in gastric tumors with and without APC mutations

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Frizzled-7 is required for Wnt signaling in gastric tumors with and without APC mutations
Title:
Frizzled-7 is required for Wnt signaling in gastric tumors with and without APC mutations
Journal Title:
Cancer Research
Keywords:
Publication Date:
08 January 2019
Citation:
Flanagan, D. J. et al. Frizzled-7 is required for Wnt signaling in gastric tumors with and without APC mutations. Cancer Res. 79, 970–981 (2019).
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. Significance: The Wnt receptor Fzd7 plays an essential role in gastric tumorigenesis irrespective of Apc mutation status, therefore targeting Wnt/Fzd7 may be of therapeutic benefit to patients with gastric cancer.
License type:
PublisherCopyrights
Funding Info:
Funding is gratefully acknowledged from the following: National Health and Medical Research Council of Australia (NHMRC, 566679, and APP1099302 awarded to E. Vincan, T.J. Phesse, and N. Barker), Melbourne Health project grants (605030 and PG-002 awarded to E. Vincan, T.J. Phesse, N. Barker and H. Clevers), Medical Research Council (MR/R026424/1 to T.J. Phesse), and Early career researcher grant (GIA-033 awarded to D.J. Flanagan), Cancer Council of Victoria project grants (CCV, APP1020716 awarded to E. Vincan, T.J. Phesse, and N. Barker), CCV Fellowship awarded to D.J. Flanagan and Cardiff University/CMU Research Fellowship awarded to T.J. Phesse.
Description:
ISSN:
0008-5472
1538-7445
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