Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution

Abstract

Gastric cancer is a major cause of global cancer mortality. To explore geospatial interactions in gastric tumors, we integrated 2,138 spatial transcriptomic regions of interest with 152,423 single-cell expression profiles across 226 cancer samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers (SOX9). Phylogenetic analysis revealed two separate evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods, including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor–stroma interfaces across multiple gastric cancers highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual gastric cancers are sculpted by tumor-intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies. Significance: Integration of spatial transcriptomic (GeoMx Digital Spatial Profiler) and single-cell RNA sequencing data from multiple gastric cancers identifies spatially resolved expression-based intratumoral heterogeneity, associated with distinct immune microenvironments. We uncovered two separate evolutionary trajectories associated with specific molecular subtypes, clinical prognoses, stromal neighborhoods, and genetic drivers. Tumor–stroma interfaces emerged as a unique state of tumor ecology.