Reciprocal Activating Interactions between Neurons and Metaplastic Acinar Cells Promote Cancer Initiation and Progression in Pancreas

Nerves are a critical component of tumor microenvironment. This study investigated the interactions between acinar-to-ductal metaplasia (ADM) and neural infiltration and their consequential impacts on the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). In various in vitro cell models and in vivo mouse models of ADM, nerves were crucial to the formation and progression of ADM, while ADM cells directly induced neural outgrowth. Gangliosides, particularly GM3, were the mediators promoting the reciprocal activating interactions between ADM cells and nerves. Consistently, the B4GALT5 gene, which encodes a key enzyme in ganglioside synthesis, was upregulated in PDAC and critically important to the ADM formation and subsequent progression to PanIN and PDAC. These findings provide novel insights into the roles of nerves and gangliosides in the early stages of PDAC pathogenesis, highlighting their potential as targets for PDAC early diagnosis and intervention, thus improving patient outcomes. Overall design: To investigate the interactions between acinar-to-ductal metaplasia (ADM) and neural infiltration and their consequential impacts on the initiation and progression of pancreatic ductal adenocarcinoma (PDAC), we then performed gene expression profiling analysis using data obtained from RNA-seq of WT and KC mice models