The role of Notch1 in K-ras induced pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers, with a five-year survival rate of less than 4%. The most commonly mutated oncogene in PDAC is K-ras. Mouse models have demonstrated that expression of activated K-ras in the pancreas is sufficient to recapitulate the entire spectrum of human disease, from premalignant lesions to the development of invasive adenocarcinoma. The Notch proteins are central components of pancreatic development. Recent studies suggest Notch signaling is reactivated during PDAC initiation and progression, leading to the supposition that Notch promotes PDAC, and therefore may represent a target for drug development. To assess whether Notch1 is required for K-ras-induced PDAC, we employed a mouse model in which oncogenic K-ras is activated and Notch1 is deleted simultaneously in the pancreas. Surprisingly, loss of Notch1 in the presence of activated K-ras led to increased tumor incidence and progression, implying Notch1 functions as a tumor suppressor in PDAC. To identify the mechanism underlying the accelerated tumor development, we investigated the role of Notch1 in acinar-to-ductal metaplasia (ADM), a precursor to the development of PDAC. Using both an in vivo mouse model and an in vitro explant culture system, we found that loss of Notch1 had no effect on ADM, suggesting Notch1 signaling regulates alternative molecular events in PDAC development. Overall these findings indicate Notch1 functions to inhibit pancreatic tumor development, and suggest that therapeutically targeting the Notch pathway may be detrimental to PDAC patients