Notch1 Is Not Required for Acinar-to-Ductal Metaplasia in a Model of Kras-Induced Pancreatic Ductal Adenocarcinoma

<div><p>Pancreatic ductal adenocarcinoma is believed to arise from precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). Mouse models have demonstrated that targeted expression of activated K-ras to mature acinar cells in the pancreas induces the spontaneous development of PanIN lesions; implying acinar-to-ductal metaplasia (ADM) is a key event in this process. Recent studies suggest Notch signaling is a key regulator of ADM. To assess if Notch1 is required for K-ras driven ADM we employed both an <em>in vivo</em> mouse model and <em>in vitro</em> explant culture system, in which an oncogenic allele of <em>K-ras</em> is activated and <em>Notch1</em> is deleted simultaneously in acinar cells. Our results demonstrate that oncogenic <em>K-ras</em> is sufficient to drive ADM both <em>in vitro</em> and <em>in vivo</em> but that loss of Notch1 has a minimal effect on this process. Interestingly, while loss of Notch1 <em>in vivo</em> does not affect the severity of PanIN lesions observed, the overall numbers of lesions were greater in mice with deleted Notch1. This suggests Notch1 deletion renders acinar cells more susceptible to formation of K-ras-induced PanINs.</p>