Abstract 6890: Subcellular 3D multi-omic models of CDH1-mutant diffuse gastric cancer improve recapitulation of tumor microenvironment structure and reveal precancer signature niches.

Abstract Diffuse-type gastric adenocarcinoma (DGC) presents as the more invasive and aggressive gastric cancer subtype with poorer prognosis. Hereditary germline CDH1 mutations are known to drive DGC in 1-3% of cases in what is known as hereditary diffuse gastric cancer (HDGC). Despite the genomic characterization of HDGC, the mechanisms of onset are still poorly understood, given that evidence suggests it can bypass the classic cascade of gastric intestinal metaplasia (IM) to dysplasia to cancer. Additionally, HDGC presents a complex tumor microenvironment (TME) given by its highly infiltrative distribution with increased immune and stromal interactions, as well as IM and dysplastic marker gene expression. These factors present an opportunity to better understand the complex cellular dynamics to elucidate the etiology of this disease. New advances in spatial transcriptomics and fluorescence imaging have reduced per-sample costs of spatial biology assays, allowing the scale necessary for studying serial sections. HDGC samples were collected as formalin-fixed, paraffin embedded blocks. Samples were serially sectioned at 5µm thickness into G4x gel pads. Regions of interest (10mm x 10mm) were isolated from the gels pads and transferred to a G4x X2 spatial flow cell. Samples were processed using Singular Genomics G4x spatial multi-omic assay with a custom pre-gastric cancer panel consisting of 16 proteins, 341 transcripts, and fluorescent-based H Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6890.