Transcriptomic profiling of a novel gastric implantation model identifies mechanisms and pathways that drive implantation into explanted human peritoneum

Abstract

Epithelial cancers such as stomach and ovarian cancer tend to metastasize to the peritoneum, often leading to intractable disease and poor survival. The mechanisms that enable gastric cancer cells to implant, invade, and survive in the peritoneal niche are poorly understood. We developed a novel human peritoneal explant model using freshly harvested peritoneal tissue samples. GFP-labeled human gastric adenocarcinoma cells (AGS) were co-cultured with the peritoneal samples, and 2% of these cells implanted into the peritoneum. The transcriptomic profile of the implanted AGS cells was compared to AGS cells that failed to implant using RNA sequencing. Differentially expressed genes in implanted AGS cells were enriched for cell adhesion and motility. We functionally validated these genes with CRISPR knockout and identified ADAM12 as a regulator of peritoneal metastasis. ADAM12 KO significantly impaired peritoneal metastasis in vivo and ex vivo and marked disruption of the ITGβ1 interactome in GCa cells. Our approach and the new data identify a distinct peritoneal metastasis gene set that facilitates the implantation and invasion of gastric cancer cells within the peritoneum. Disruption of these pathways with peritoneal-directed therapies has the potential to improve survival in patients with high-risk primary gastric cancer.