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Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) represents the most commonly diagnosed precursor lesion of pancreatic ductal adenocarcinoma (PDA), however the cell-of-origin remains unclear. Herein, we show that pancreas-specific activation in mice of nuclear-targeted glycogen synthase kinase-3β and oncogenic KRasG12D leads to the loss of acinar cells, the expansion of ductal cells, and the rapid development of IPMN with low-grade dysplasia. RNA-sequencing identified the expression of several ductal stem cell lineage genes including the water channel AQP5. The Aqp5+ pancreatic ductal cell pool was proliferative, phenotypically distinct from mature pancreatic ductal cells, and deletion of AQP5 limited IPMN development. Significantly, Aqp5 is highly expressed in human IPMN along with GSK-3b suggesting that human preneoplastic lesions likely arise from the expansion of an Aqp5+ pancreatic ductal stem cell. Altogether, these data identify Aqp5+ ductal cells in the mouse and human pancreas as the likely cell-of-origin for IPMN.

ORGANISM(S): Mus musculus

PROVIDER: GSE169618 | GEO | 2022/03/22

REPOSITORIES: GEO

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Project description:Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are cyst-like precursor lesions that give rise to 25% of pancreatic ductal adenocarcinomas (PDAC). While ~90% of cases are diagnosed before cancer forms, metrics and markers by which to determine if an IPMN will progress are currently lacking. Overall, 96% of IPMNs harbor KRAS (~80%) and/or GNAS (~66%) driver mutations and IPMN may be classified as either gastric, intestinal, or pancreatobiliary type. Recently, we identified a shared program of pyloric type metaplasia between pancreatic and gastric injury. Here, we combined immunostaining, RNA-sequencing, molecular biology, and analysis of patient samples to identify major drivers of this program in IPMN. Methods Single cell RNA-sequencing datasets of human IPMN were assayed for markers of pyloric-type metaplasia. 37 IPMN patient samples were immunostained using MxIHC for MUC5AC, CD44v9, and AQP5. KrasG12D and GnasR201C expression was modified in IPMN cell lines to identify transcriptomic programs driven by each oncogene, and in combination. Gene sets were compared to murine and human gastric cell types. Transcriptomic drivers were identified and manipulated in vitro. Candidate driver expression was evaluated by immunostaining of patient IPMN and graded. Results Analysis of published bulk and scRNA-seq IPMN datasets revealed expression of previously described markers of pyloric type metaplasia. Marker expression was confirmed in patient samples. Manipulation of KrasG12D and GnasR201C expression in IPMN cell lines identified the relative contributions of each oncogene to this gastric phenotype. Regulon analysis suggests that transcription factors SPDEF, CREB3L1, and CREB3L4 amplify this program in response to GnasR201C expression. All transcription factors were expressed in patient IPMN samples. Conclusions In response to oncogenic mutation(s), IPMN form in the pancreas and express markers of pyloric type metaplasia. KrasG12D and GnasR201C expression drive this program through independent and synergistic mechanisms that result in amplified expression of mucins and gastrokines, consistent with the phenotype identified in vivo.

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Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

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