Drug-Induced p53 Activation Promotes Acinar Cell Identity and Prevents Pancreatic Cancer Initiation

Abstract

AbstractPancreatitis is a painful inflammatory disease that carries an increased risk of developing pancreatic cancer. Patients with this disease experience acinar-to-ductal metaplasia (ADM), a process in which their pancreatic acinar cells dedifferentiate into a more ductal-like state. Metaplastic cells can proliferate and repopulate the pancreas before redifferentiating into functional acini. However, when metaplastic cells develop activating mutations in the oncogene Kras, they can progress into pancreatic intraepithelial neoplasias (PanINs). p53 has been recently shown to limit ADM, yet the underlying mechanisms of this function has not been explored in detail. Here, by treating mouse models of acute pancreatitis with Nutlin-3a (a non-genotoxic inducer of p53), we have found that mild p53 activation can significantly preserve functional acinar cells and restrain the formation of premalignant lesions. Our results also show that mild p53 activation can mitigate mutant Kras-prompted proliferation without adversely affecting the regeneration of acinar cells following pancreatitis. Leveraging a novelin vivosystem to label metaplastic cells, we observe ADM redifferentiation into acini following treatment with Nutlin-3a, unequivocally establishing a new role of p53 in inducing ADM redifferentiation. Our data indicate that this role is mediated through the acinar transcription factor Mist1, which we highlight as a novel p53 target gene. Our findings also suggest that MDM2 inhibitors hold promise as a therapeutic approach for individuals at risk of developing pancreatic adenocarcinoma, including patients with pancreatitis.