Abstract
The majority of gastric cancer cells proliferate in a Wnt ligand-dependent manner. To investigate this, we generated mice harboring Kras, Tgfbr2, and Trp53 (KTP) as well as with the same mutations plus Wnt1 expression (WKTP) in gastric mucosa. While KTP mice develop gastric metaplasia, WKTP mice develop dysplastic tumors, highlighting the role of ligand-dependent Wnt signaling in primary tumorigenesis. Organoids derived from WKTP mice form liver metastases following splenic transplantation, whereas KTP organoids do not. Notably, Apc disruption fails to induce metastasis of KTP cells, suggesting that stromal Wnt signaling promotes metastasis. Mechanistically, tumor-derived Wnt ligands cooperate with TGFβ signaling to induce Has2 expression in cancer-associated fibroblasts (CAFs), leading to hyaluronan accumulation in the metastatic microenvironment. Strikingly, hyaluronidase expression in WKTP cells significantly suppresses liver metastasis. Here we show the critical role of ligand-dependent Wnt signaling and Has2-mediated hyaluronan deposition in metastasis, offering potential therapeutic strategy against gastric cancer metastasis.
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Data availability
The spatial transcriptomics (Visium) data generated in this study have been deposited in the DDBJ under the BioProject accession number PRJDB20422 and Run accession number DRR656668. Source data underlying Figs. 1c, e, g, 2c, f, 3c, f, i, 4c, d, g, 5c, e, 6b, c, d, f, and 7a, b, d, g, as well as Supplementary Figs. 1, 2d, 6b, 7c, 8a, b, and 9a are provided in the Source Data file with this paper. All other data supporting the findings of this study are available within the Article and its Supplementary Information. Any additional materials, including mouse models and organoids, are available from the corresponding authors upon completion of a material transfer agreement. Source data are provided with this paper.
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Acknowledgements
We thank Manami Watanabe and Ayako Tsuda for their technical assistance. This work was supported by Grants-in-Aid for Scientific Research (A) (22H00454 to M.O.) and (B) (23K02899 to H.O.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; AMED (24ama22152h0002 to H.O.) from the Japan Agency for Medical Research and Development, Japan.
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Y.F., H.O., R.M., M.N., and K.M. performed experiments; C.P.H. and SJ.C. performed bioinformatics analysis; S.Y., Y.I., and D.M. analyzed patient materials; H.O. and N.B. generated mouse models; H.O., N.I, and M.O. discussed results; M.O. supervised research; H.O. and M.O. wrote the manuscript.
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Furutani, Y., Oshima, H., Hong, C.P. et al. Ligand-dependent Wnt signaling promotes gastric cancer metastasis through hyaluronan expression in microenvironment. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69470-5
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DOI: https://doi.org/10.1038/s41467-026-69470-5
