Investigation of the mechanism of duodenal cancer progression using a novel mouse model

Aim: Duodenal adenocarcinoma is a rare malignancy, and its mechanisms of tumorigenesis remain poorly understood. This study aimed to elucidate the mechanisms of tumor progression and establish a foundation for the clinical application of inhibitors using a novel PIK3CA mutated duodenal tumor mouse model.Methods: The progression of tumorigenesis in the mouse model was analyzed histologically. Tumor-derived organoids were established, and RNAseq analysis was performed to identify differentially expressed genes, followed by functional analysis. Furthermore, findings were validated using clinical specimens.Results: In this mouse model, elevated tumor lesions appeared in the duodenal bulb from two months of age, progressively enlarging over time. By eight months of age, submucosal invasion were frequently observed. Histological analysis revealed that the tumors were MUC2 positive intestinal-type adenocarcinomas. RNAseq analysis revealed a significant downregulation of GATA4 expression. Decreased GATA4 expression in the invasive tumor areas was also confirmed in both the mouse model and clinical specimens. Forced overexpression of GATA4 in the tumor organoids resulted in the suppression of epithelial mesenchymal transition related genes. Furthermore, enhanced sensitivity to Akt inhibitor capivasertib was observed (IC50: 2.32 vs. 0.64 µM).Conclusion: The PIK3CA mutation was identified as a driver mutation in duodenal adenocarcinoma, and the therapeutic efficacy of Akt inhibitors was suggested. Additionally, GATA4 downregulation may contribute to tumor progression and drug resistance.