High-resolution Spatial Transcriptomics Reveals Contrasting Tumor States in Two Early Gastric Cancers

Intratumoral heterogeneity is a major feature of gastric cancer (GC), but its spatial organization remains incompletely understood. We applied high-resolution spatial transcriptomics to two histologically contrasting early GCs.

One formalin-fixed, paraffin-embedded specimen from a gastric adenocarcinoma of fundic-gland type and one from a signet-ring cell carcinoma with signet-ring and non-signet poorly cohesive components were analyzed using Visium HD. All comparisons were made between clusters within each section.

Spatial clustering recapitulated histological architecture in both tumors. The fundic-gland type adenocarcinoma formed a predominantly single epithelial cluster with lower predicted developmental potential than the normal isthmus, and limited inferred signaling with adjacent tissues. Within the signet-ring cell carcinoma, the poorly cohesive component showed higher predicted developmental potential, increased stem cell-associated markers, and oxidative phosphorylation enrichment, whereas the signet-ring component showed epithelial-mesenchymal transition enrichment (likely reflecting stromal admixture) and higher ANXA10 expression. Distinct APP- and CEACAM-related communication patterns were predicted.

In these two tumors, high-resolution spatial transcriptomics resolved histologically distinct tumor states and microenvironmental compartments within individual lesions. The findings are descriptive and hypothesis-generating rather than subtype-defining and require validation in larger cohorts.