Epithelial WNT secretion drives niche escape of developing gastric cancer

Mol Cancer. 2025 Dec 16;25(1):1. doi: 10.1186/s12943-025-02543-z.

Abstract

Background: WNT signaling plays a key role in maintaining the gastric epithelium and promoting tumorigenesis. However, how gastric tumors achieve WNT niche independence remains unclear, as mutations on APC or CTNNB1-common mechanisms of ligand-independent WNT activation in colorectal cancer-are infrequent in gastric cancer. Understanding how WNT self-sufficiency is acquired in the stomach is therefore critical.

Methods: We analyzed mouse gastric organoids harboring oncogenic KRASG12D with or without RNF43/ZNRF3 (RZ) or CDH1/TP53 (CP) mutations, along with corresponding in vivo mouse models. Niche independence was assessed through growth factor withdrawal, Porcupine and pathway-specific inhibitor treatments, and WNT rescue assays. We performed single-nucleus multiome sequencing (RNA + ATAC) to investigate transcriptional and chromatin dynamics. Findings from mouse models were validated using patient-derived gastric cancer organoids, and pan-cancer cell line datasets were analyzed to evaluate clinical and cross-tissue relevance.

Results: Gastric fibroblasts secreted canonical WNT2B to maintain the homeostatic gastric epithelium. Upon KRAS activation, epithelial cells were reprogrammed to secrete WNT ligands independently of additional mutations. Single-nucleus multiome analysis revealed that KRAS-driven MAPK signaling opened SMAD2/3-bound enhancers at the WNT7B locus, leading to the emergence of WNT7B-expressing subpopulations. Inhibition of SMAD2/3 phosphorylation suppressed both organoid growth and WNT7B transcription, whereas exogenous WNT restored organoid proliferation. Patient-derived organoids with HER2 amplification, KRAS amplification, or WNT2 copy-number gain exhibited Porcupine inhibitor-sensitive growth, indicating dependence on WNT secretion from the organoids. Analysis of public transcriptomic datasets further demonstrated that the KRAS-MAPK-WNT7B axis is conserved across other cancer types, including lung cancer.

Conclusions: Gastric tumors can bypass niche dependence by acquiring KRAS-MAPK-SMAD2/3-driven epithelial WNT secretion. Targeting this axis-through MAPK inhibition, SMAD2/3 blockade, or suppression of WNT secretion-may represent a therapeutic vulnerability in gastric cancer and other KRAS-high malignancies.

Keywords: Gastric cancer; KRAS–MAPK–WNT7B axis; Tumor microenvironment; WNT self-sufficiency.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Epithelial Cells* / metabolism
  • Epithelial Cells* / pathology
  • Humans
  • Mice
  • Mutation
  • Organoids / metabolism
  • Stomach Neoplasms* / etiology
  • Stomach Neoplasms* / genetics
  • Stomach Neoplasms* / metabolism
  • Stomach Neoplasms* / pathology
  • Wnt Proteins* / genetics
  • Wnt Proteins* / metabolism
  • Wnt Signaling Pathway*

Substances

  • Wnt Proteins