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

Abstract

ABSTRACTOBJECTIVEIntraductal 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.DESIGNWe analyzed RNA-seq studies of IPMN for pyloric markers, which were validated by immunostaining in patient samples. Cell lines expressingKrasG12D+/−GNASR201Cwere 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.RESULTSPyloric markers were identified in human IPMN.GNASR201Cdrove expression of these markers in cell lines and siRNA targeting ofGNASR201CorKrasG12Ddemonstrates thatGNASR201Camplifies a mucinous, pyloric phenotype. Regulon analysis identified a role for transcription factors SPDEF, CREB3L1, and CREB3L4, which are expressed in patient samples. siRNA-targeting ofSpdefinhibited mucin production.CONCLUSIONDe novoexpression of a SPEM phenotype has been identified in pancreatitis and a pyloric phenotype inKrasG12D-driven PanIN andKrasG12D;GNASR201C-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-specificGNASR201Camplifies a mucinous phenotype, in part, through SPDEF.