Targeting of E-cadherin-negative diffuse-type gastric cancer

PROJECT SUMMARY/ABSTRACT Gastric cancer is the fourth most common cause of cancer deaths worldwide, with five-year survival rates of slightly over 20%. More than 90% of gastric cancer cases belong to gastric adenocarcinoma (GAC), which can be further divided into intestinal-type gastric cancer (IGC) and diffuse-type gastric adenocarcinoma (DGAC). While the overall incidence of GC has decreased, the incidence rate of DGAC is increasing. Unlike IGC, DGAC is more commonly observed in younger patients, females, and the Hispanic populations. DGAC is aggressive and tends to be detected at later stages, resulting in poor prognosis and limited treatment options. DGAC is resistant to systemic therapy, and the progress toward targeted therapy for DGAC treatment is relatively slower. Additionally, biomarker-guided therapeutic options are limited. Therefore, the development of a new therapy is crucial. The proposed study aims to unravel the mechanisms of DGAC tumorigenesis and apply that knowledge to laying a foundation for DGAC therapy development. To address this, we established a model system that recapitulates human DGAC tumorigenesis using genetically engineered gastric organoids and transplantation approaches. Single-cell transcriptomics helped us delineate the cell dynamics, cells of origin, and cell plasticity of DGAC. Our findings led us to identify potential drugs that target the root cells driving the neoplastic cell lineage of DGAC. Based on the preliminary results, we hypothesize that drugs identified by single-cell transcriptomics inhibit neoplastic cell lineages and suppress E-cadherin-negative DGAC tumorigenesis, which will be tested by pursuing the following aim: To determine the impact of drug candidates on DGAC stemness, tumorigenesis, and first-line treatment. Completing the proposed study will lay a novel foundation for DGAC therapy development by determining whether targeting specific cell clusters inhibits E-cadherin-negative DGAC tumorigenesis.