Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas.

Objective: Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to ductal metaplasia, an injury repair program, is characterized by a transcriptomic program similar to gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach and pancreas. The aims of this study were to assay IPMN for pyloric markers and to identify molecular drivers of this program.

Design: We analyzed RNA-seq studies of IPMN for pyloric markers, which were validated by immunostaining in patient samples. Cell lines expressing +/- were manipulated to identify distinct and overlapping transcriptomic programs driven by each oncogene. A PyScenic-based regulon analysis was performed to identify molecular drivers in the pancreas. Expression of candidate drivers was evaluated by RNA-seq and immunostaining.

Results: Pyloric markers were identified in human IPMN. drove expression of these markers in cell lines and siRNA targeting of or demonstrates that amplifies a mucinous, pyloric phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. siRNA-targeting of inhibited mucin production.

Conclusion: expression of a SPEM phenotype has been identified in pancreatitis and a pyloric phenotype in -driven PanIN and -driven IPMN, suggesting common mechanisms of reprogramming between these lesions and the stomach. A transition from a SPEM to pyloric phenotype may reflect disease progression and/or oncogenic mutation. IPMN-specific amplifies a mucinous phenotype, in part, through SPDEF.