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Mandigers, P. J.

Publications and source records attributed to Mandigers, P. J..

2 recordsLinked to original sources
bioRxiv2026

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

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.

genomics↗
bioRxiv2024

Genomic analyses identify 15 susceptibility loci and reveal HDAC2, SOX2-OT, and IGF2BP2 in a naturally-occurring canine model of gastric cancer

Gastric cancer (GC) is the fifth most common human cancer worldwide, but the genetic etiology is largely unknown. We performed a Bayesian genome-wide association study and selection analyses in a naturally-occurring canine model of GC, the Belgian Tervuren and Sheepdog breeds, to elucidate underlying genetic risk factors. We identified 15 loci with over 90% predictive accuracy for the GC phenotype. Variant filtering revealed germline putative regulatory variants for the EPAS1 (HIF2A) and PTEN genes and a coding variant in CD101. Although closely related to Tervuren and Sheepdogs, Belgian Malinois rarely develop GC. Across-breed analyses uncovered protective haplotypes under selection in Malinois at SOX2-OT and IGF2BP2. Among Tervuren and Sheepdogs, HDAC2 putative regulatory variants were present at comparatively high frequency and were associated with GC. Here, we describe a complex genetic architecture governing GC in a dog model, including genes such as PDZRN3, that have not been associated with human GC.

genomics↗