Ligand-dependent Wnt signaling promotes gastric cancer metastasis through hyaluronan expression in microenvironment

The majority of gastric cancer cells proliferate in a Wnt ligand-dependent manner. In this study, we examined the role of ligand-dependent Wnt signaling in the development and metastasis of gastric cancer. We generated mice with mutations in Kras , Tgfbr2 , and Trp53 (KTP mice) as well as mice with the same mutations plus Wnt1 expression (WKTP mice) in gastric mucosa. KTP mice displayed gastric metaplasia with parietal cell loss, whereas WKTP mice developed dysplastic tumors, highlighting the role of ligand-dependent Wnt signaling in the initial stage of primary gastric cancer. Subsequently, we established organoids from the gastric epithelia of KTP and WKTP mice and transplanted them into the mouse spleens. Notably, only WKTP organoids formed liver metastases. Interestingly, Apc disruption did not induce metastasis of KTP cells, suggesting that Wnt signaling in stromal cells may contribute to metastasis. Spatial transcriptomic analysis confirmed Wnt signaling activation in the stroma of metastatic tumors. Furthermore, Wnt ligands and TGFβ synergistically activate hepatic stellate cells (HSCs), converting them into cancer-associated fibroblasts (CAFs) and inducing expression of hyaluronan synthase Has2 . Consistent with the finding, significant hyaluronan deposition was observed in liver metastases of both mouse and human gastric cancers. Notably, the expression of hyaluronidase in WKTP cells significantly suppressed liver metastasis. These results indicate that Wnt ligands ,in conjunction with TGFβ, activate HSCs/CAFs to induce Has2 expression, which promotes metastatic tumor development through hyaluronan deposition. Consequently, inhibiting of ligand-dependent Wnt signaling or Has2 expression may represent an effective strategy for preventing or treating gastric cancer metastasis.