Inactivation of Attenuated Pancreatic Tumorigenesis in Mice.

UNLABELLED

Expression of the Notch family of receptors is often upregulated in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on Notch4, which had not been investigated in PDAC. We generated KC (), N4 KC (), PKC (), and N4 PKC () genetically engineered mouse models (GEMM). We performed caerulein treatment in both KC and N4 KC mice, and the development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions were significantly diminished in the N4 KC than in the KC GEMM ( = 0.01). This result was validated by ADM induction of the explant cultures of pancreatic acinar cells from the N4 KC and KC mice ( < 0.001), confirming that Notch4 is an important contributor to early pancreatic tumorigenesis. To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the PKC and N4 PKC mice. The N4 PKC mice had better overall survival ( = 0.012) and significantly reduced tumor burden (PanIN: = 0.018 at 2 months, PDAC: = 0.039 at 5 months) compared with the PKC GEMM. RNA-sequencing analysis of pancreatic tumor cell lines derived from the PKC and N4 PKC GEMMs revealed that 408 genes were differentially expressed (FDR < 0.05) and is a potential downstream effector of the Notch4 signaling pathway ( < 0.001). Low expression of Pcsk5 positively correlates with good survival in patients with PDAC ( = 0.028). We have identified a novel role for Notch4 signaling with tumor-promoting function in pancreatic tumorigenesis. Our study also uncovered a novel association between and Notch4 signaling in PDAC.

SIGNIFICANCE

We demonstrated that global inactivation of significantly improved the survival of an aggressive mouse model for PDAC and provided preclinical evidence that Notch4 and Pcsk5 are novel targets for PDAC therapies.