A multi-modal transcriptomic atlas reveals the cellular and spatial landscape of canine gastric cancer

Abstract

Gastric cancer is the fifth leading cause of cancer-related mortality in humans globally and remains a clinical challenge with limited treatment options and poor survival. Dogs develop spontaneous gastric cancer that parallels the clinical presentation and histology of human disease, supporting their value as a comparative oncology model. Here we present a comprehensive transcriptomic characterization of canine gastric cancer through single-nucleus RNA-sequencing, bulk RNA-sequencing, and Visium HD 3' spatial transcriptomics of treatment-naive tumor and normal stomach tissues from Belgian Tervuren and Belgian Sheepdogs. Across 107,085 nuclei, we identified 44 distinct cell populations, including tumor-enriched states as well as profound depletion of the normal parietal and chief cell gastric lineages. Cell-cell communication analysis revealed enhanced epithelial-fibroblast crosstalk driving epithelial-mesenchymal transition. Bulk RNA-sequencing further identified enrichment of signaling pathways implicated in H. pylori associated human gastric carcinogenesis, including Hippo, PI3K-Akt, and Wnt. Notably, we observed cell-type-specific altered expression of KLHL29, PDZRN3, and PLAU, which are among our previously identified canine gastric cancer susceptibility genes, linking germline risk to specific tumor cellular contexts. These data establish the first transcriptomic atlas of canine gastric cancer and demonstrate substantial molecular homology between canine and human disease.