Epithelial Notch signaling is a limiting step for pancreatic carcinogenesis

Abstract

Background: Pancreatic cancer is one of the deadliest human malignancies, with few therapeutic options. Re-activation of embryonic signaling pathways is commonly in human pancreatic cancer and provided rationale to explore inhibition of these pathways therapeutically. Notch signaling is important during pancreatic development, and it is re-activated in pancreatic cancer. The functional role of Notch signaling during pancreatic carcinogenesis has been previously characterized using both genetic and drug-based approaches. However, contrasting findings were reported based on the study design. In fact, Notch signaling has been proposed to act as tumor-promoter or tumor-suppressor. Given the availability of Notch inhibitors in the clinic, understanding how this signaling pathway contributes to pancreatic carcinogenesis has important therapeutic implications. Here, we interrogated the role of Notch signaling specifically in the epithelial compartment of the pancreas, in the context of a genetically engineered mouse model of pancreatic cancer. Methods: To inhibit Notch signaling in the pancreas epithelium, we crossed a mouse model of pancreatic cancer based on pancreas-specific expression of mutant Kras with a transgenic mouse that conditionally expresses a dominant negative form of the Mastermind-like 1 gene. MAML is an essential co-activator of the canonical Notch signaling-mediated transcription. DNMAML encodes a truncated MAML protein that represses all canonical Notch mediated transcription in a cell autonomous manner, independent of which Notch receptor is activated. As a result, in mice co-expressing mutant Kras and DNMAML, Notch signaling is inhibited specifically in the epithelium upon Cre-mediated recombination. We explored the effect of epithelial-specific DNMAML expression on Kras-driven carcinogenesis both during normal aging and following the induction of acute pancreatitis. Results: We find that DNMAML expression efficiently inhibits epithelial Notch signaling and delays PanIN formation. However, over time, loss of Notch inhibition allows PanIN formation and progression. Conclusions: Epithelial-specific Notch signaling is important for PanIN initiation. Our findings indicate that PanIN formation can only occur upon loss of epithelial Notch inhibition, thus supporting an essential role of this signaling pathway during pancreatic carcinogenesis.