Expression of the Notch family of receptors are often upregulated in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on Notch4, which had not been investigated in PDAC. We generated KC (LSL-KrasG12D;p48-Cre), N4-/-KC (Notch4-/-;LSL-KrasG12D;p48-Cre), PKC (p16fl/fl;LSL-KrasG12D;p48-Cre), and N4-/-PKC (Notch4 -/-; p16fl/f l;LSL-KrasG12D;p48-Cre) genetically engineered mouse models (GEMMs). 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 (p=0.01). This in vivo result was validated by in vitro ADM induction of the explant cultures of pancreatic acinar cells from the N4-/-KC and KC mice (p<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 (p=0.012) and significantly reduced tumor burden (PanIN: p=0.018 at 2 months, PDAC: p=0.039 at 5 months) compared to the PKC GEMM. RNA-Seq analysis of pancreatic tumor cell lines derived from the PKC and N4-/-PKC GEMMs revealed 408 genes were differentially expressed (FDR<0.05) and Pcsk5 as a potential downstream effector of the Notch4 signaling pathway (p<0.001). Low expression of Pcsk5 positively correlates with good survival in PDAC patients (p=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 Pcsk5 and Notch4 signaling in PDAC.

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Supplementary data