Abstract
328 Background: ARID1A, a member of the SWI/SNF chromatin-remodeling complex, is mutated in up to 30% of pancreatic ductal adenocarcinoma (PDAC). Here, we studied the effect of Arid1a loss in pancreatic tumorigenesis in the setting of a constitutively activated Kras allele ( KrasG12D), which is the basis of a well-established mouse model of pancreas cancer. Methods: Arid1a was deleted during embryogenesis in acinar, duct, and islet cells in Ptf1a-Cre; Arid1af/f (CA) and KrasG12D; Ptf1a-Cre; Arid1a f/f (KCA) mice. Arid1a was inducibly deleted in adult mice specifically in duct or acinar cells with KrasG12D; Sox9-CreER; Arid1a f/f (KSERA), and KrasG12D; Ptf1a-CreER; Arid1a f/f (KPERA) mice, respectively. Tamoxifen was given at 4 weeks of age. Results: Genotyping of CA mice toes and pancreata showed Arid1a loss only in the latter confirming pancreas-specific recombination. Western blot confirmed decreased protein expression and immunohistochemistry (IHC) demonstrated Arid1a loss in most of the acini and half of the ducts. ~35% of CA mice developed benign appearing cysts by 4 months. KCA mice had macroscopic cysts by 3 weeks. The cyst fluid was thick and amylase rich. These cysts resembled intraductal papillary mucinous neoplasm (IPMN) as they had papillary features and stained for Alcian blue, confirming the presence of mucin. Muc protein staining pattern was consistent with pancreaticobiliary type IPMN. The stroma was negative for estrogen and progesterone receptors. KSERA mice developed large mucin producing ductal lesions by 12 weeks while only pancreatic intraepithelial neoplasias were seen in KPERA mice. Conclusions: Arid1a loss in the pancreas leads to pancreaticobiliary IPMN that appear to arise from the duct cells. Future directions include aging studies to determine if these cysts transform to frank PDAC, determining the status of ARID1A in human IPMN, and elucidating the mechanisms for cyst formation. Finally, this model may be useful as a platform to test therapeutic interventions to treat IPMN.
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