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Ductal obstruction promotes formation of pre-neoplastic lesions from the pancreatic ductal compartment.

Pancreatitis is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice have demonstrated that pancreatitis contributes to oncogenic Kras-driven carcinogenesis, probably initiated in acinar cells; however, oncogenic Kras alone or in combination with caerulein-induced pancreatitis is not sufficient in initiating PDAC from the ductal compartment. We thus introduced ductal obstruction - which induces a more severe form of pancreatitis - by pancreatic ductal ligation in mice harbouring oncogenic Kras. This induced a particular phenotype with highly proliferative non-mucinous cells with nuclear atypia. Around these lesions, there was a significant proliferation of activated fibroblasts and infiltration of immune cells, corroborating the pathological features of pre-neoplastic lesions. Lineage-tracing experiments revealed that these pre-neoplastic cells derived from two distinctive cellular sources: acinar and ductal cells. Phenotypic characterisation revealed that the duct-derived pre-neoplastic lesions show a high proliferative potential with persistent activation of tumour-promoting inflammatory pathways while the acinar-derived ones were less proliferative with persistent p53 activation. Furthermore, the duct-derived pre-neoplastic cells have a particularly high nuclear-to-cytoplasmic ratio. These data demonstrate that ductal obstruction promotes pre-neoplastic lesion formation from the pancreatic ductal compartment. This article is protected by copyright. All rights reserved.

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