Ganglioside-Mediated Neural-Acinar Crosstalk Facilitates Pancreatic Carcinogenesis via Metaplastic Niche Remodeling.

Neural networks constitute a crucial component of the tumor microenvironment that remains underexplored in pancreatic carcinogenesis. This study systematically investigated the reciprocal interactions between acinar-to-ductal metaplasia (ADM) and neural remodeling during pancreatic ductal adenocarcinoma (PDAC) initiation and progression. Multimodal approaches combining in vitro culture systems and mouse models of ADM were used to characterize neurotrophic effects. State-of-the-art mass spectrometry-based lipidomic profiling was performed on ADM, pancreatic intraepithelial neoplasia, and PDAC lesions and conditioned cell cultures. Complementary analyses integrating single-cell RNA sequencing data and genetic perturbation experiments (gene overexpression and knockdown) were conducted across murine and human cell lines and tissue specimens using immunohistochemical validation and immunoblotting. Inflammation and Kras mutation induced ADM in pancreas. Metaplastic epithelial cells actively induced neuritogenesis, and neural remodeling processes critically impacted ADM formation. Mechanistically, this bidirectional crosstalk was mediated by ganglioside metabolites, particularly GM3 as the principal mediator. Systematic interrogation of ganglioside biosynthesis pathways revealed that β-1,4-galactosyltransferase 5 overexpressed in mouse and human pancreatic lesions of ADM, pancreatic intraepithelial neoplasia, and PDAC, and functional studies established its essential role in ADM initiation and subsequent progression to pancreatic intraepithelial neoplasia and invasive PDAC. Pharmacologic inhibition of β-1,4-galactosyltransferase 5 attenuated neuronal growth and reverse ADM formation and progression. This work elucidates a previously unrecognized paracrine circuit linking neural plasticity with epithelial reprogramming through ganglioside signaling, providing mechanistic insights into microenvironmental regulation of early pancreatic carcinogenesis. Our findings position neuronal-ADM interactions and glycosphingolipid metabolism as promising therapeutic targets for intercepting PDAC development at premalignant stages.