In summary, our data show that deregulated Hh/Gli2 signaling in Lgr5+ stem cells is sufficient to drive invasive gastric adenocarcinoma development in mice, point to a potential role for Hh/Gli signaling in a subset of human gastric cancers, underscore the functional significance of crosstalk between the Hh/Gli2 and mTOR signaling pathways in cancer, and highlight the divergent responsiveness of gastric versus intestinal Lgr5+ epithelial stem cells to oncogenic Hh signaling. Here, LGR5 is linked to gastric cancer.