Stromal Hedgehog signaling drives segment-specific malignant transformation of gastrointestinal stem cells by producing BMP antagonists.

BACKGROUND & AIMS: Hedgehog (HH) signaling plays a complex role in epithelial-stromal interactions, but its effects on gastrointestinal stem cells mediated by heterogeneous stromal cell populations remain incompletely defined. Here, we investigate how stromal HH signaling regulates gastric stem cells and tumorigenesis in a segment-specific manner. METHODS: We genetically activated HH signaling in distinct stromal cell lineages using Col1a2-, Pdgfra-, Gli1-, Acta2-, and Prrx1-CreERT mouse lines, combined with lineage tracing, RNA-seq, ChIP-qPCR, and pharmacological interventions. Human gastric cancer data from TCGA were also analyzed. RESULTS: We show that genetic activation of HH signaling in stromal cells marked by Col1a2, Pdgfra, or Gli1, but not by Acta2, induces tumorigenesis in the stomach and gastroesophageal junction, but not in small or large intestine. HH signaling increases the expression of multiple BMP antagonists in gastric but not colonic stromal cells, via Gli1-mediated transcription. These BMP antagonists in turn activate Wnt/β-catenin signaling in gastric stem cells, driving their proliferation and initiating gastric cancer expressing CD44 and Sox9, but not Lgr5. Activating BMP or inhibiting Wnt signaling blocks tumor initiation. TCGA patient data analysis reveals elevated HH signaling in gastric cancers, which correlates with suppressed BMP signaling. CONCLUSIONS: These findings uncover a gastrointestinal segment-specific oncogenic role for HH signaling in Col1a2+Acta2- stromal cells, mediated through the BMP-Wnt/β-catenin axis.