配体依赖性Wnt信号驱动胃癌转移龛的形成

Gastric cancer remains among the most common and lethal malignancies worldwide, and survival rate for stage IV patients is still significantly low, underscoring the need for novel preventive and therapeutic strategies. Recent studies using patient-derived organoids indicate that, in many gastric cancers, Wnt signaling is activated through an exogenous, ligand-dependent mechanism despite the absence of APC or CTNNB1 mutations. Here, we investigated how ligand-dependent Wnt signaling contributes to gastric cancer development and metastasis. We generated genetically engineered mouse models (KTP mice) carrying Kras G12D, Tgfbr2 -/-, Trp53 R270H mutations in the gastric epithelial cells, as well as with the same mutations plus Wnt1 expression (WKTP mice). Whereas KTP mice developed gastric metaplasia, WKTP mice developed dysplastic tumors, suggesting that ligand-dependent Wnt signaling promotes primary tumorigenesis. In metastasis analysis, organoids derived from WKTP mouse tumors formed liver metastases after splenic transplantation, while KTP organoids did not. Notably, genetic disruption of Apc was insufficient to confer metastatic capacity on KTP cells, suggesting that Wnt signaling activation in stromal cells is critical for metastasis. Mechanistically, tumor-derived Wnt ligands cooperated with TGF-beta induce Has2 expression in stromal fibroblasts (CAFs), resulting in hyaluronan accumulation within the liver metastatic niche. Importantly, enforced hyaluronidase expression in cancer cells markedly suppressed liver metastasis. These results indicate a pivotal role of ligand-dependent Wnt signaling in the CAFs in gastric cancer metastasis through Has2-mediated hyaluronan deposition. Therefore, targeting Wnt signaling/Has2-hyaluronan axis may be a potential therapeutic strategy against metastatic gastric cancer.