Abstract
Background & aims:
Intraductal tubulopapillary neoplasm (ITPN) is a rare, high-grade tumor of the pancreatic duct, characterized by distinct molecular features including frequent alterations in the components of switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex and PI3K/AKT pathways. This study aimed to investigate the functional role of BRG1, a key SWI/SNF component, in pancreatic ductal cells, particularly in the context of PI3K/AKT pathway activation.
Methods:
We generated conditional knockout mice by crossing Hnf1b-CreERT2, Brg1flox, and Ptenflox strains. Pancreatic organoids were used for subcutaneous xenografts in NOD/SCID mice. Twelve human ITPN specimens were analysed by immunohistochemistry.
Results:
In the context of PI3K/AKT pathway activation, Brg1 deletion in pancreatic ductal cells led to the development of ITPN accompanied by invasive carcinoma components. An upregulation of the Yes-associated protein 1/transcriptional coactivator with the PDZ-binding motif (YAP/TAZ) pathway was observed in mutant pancreatic ductal cells. In the xenograft model, pancreatic tumour organoids progressed into invasive pancreatic ductal adenocarcinoma (PDAC) with high TAZ expression, indicating sustained YAP/TAZ pathway activation. Furthermore, administration of verteporfin, a YAP/TAZ pathway inhibitor, reduced tumour formation and partially reversed the dedifferentiation of pancreatic ductal cells. Consistent with the mouse data, analysis of 12 human ITPN specimens showed frequent downregulation of SWI/SNF components, with a significant inverse correlation between BRG1 and TAZ expression.
Conclusions:
Simultaneous loss of Brg1 and Pten in pancreatic ductal cells results in ITPN formation via the activation of the YAP/TAZ pathway in the mouse model. The YAP/TAZ pathway is a key driver of ITPN formation and is a potential therapeutic target for ITPN and ITPN-derived PDAC.