Data from Inactivation of <i>Notch4</i> Attenuated Pancreatic Tumorigenesis in Mice

• DOI: 10.1158/2767-9764.c.6551189.v1
• Publication Date: 2023-04-04T19:32:20Z
• Authors: Kiyoshi Saeki; Wanglong Qiu; Richard A. Friedman; Samuel Pan; Jordan Lu; Shu Ichimiya; Iok In Christine ...; Carrie J. Shawber; Jan Kitajewski; Jianhua Hu; Gloria H. Su

<div><p>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.</p><p>We generated KC (<i>LSL-Kras^G12D;p48-Cre</i>), N4<i>⁻^/⁻</i>KC (<i>Notch4⁻^/⁻;LSL-Kras^G12D;p48-Cre</i>), PKC (<i>p16^fl/fl;LSL-Kras^G12D;p48-Cre</i>), and N4<i>⁻^/⁻</i>PKC (<i>Notch4^−/⁻; p16^fl/f^l;LSL-Kras^G12D;p48-Cre</i>) genetically engineered mouse models (GEMM). We performed caerulein treatment in both KC and N4<i>⁻^/⁻</i>KC mice, and the development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions were significantly diminished in the N4<i>⁻^/⁻</i>KC than in the KC GEMM (<i>P</i> = 0.01). This <i>in vivo</i> result was validated by <i>in vitro</i> ADM induction of the explant cultures of pancreatic acinar cells from the N4<i>⁻^/⁻</i>KC and KC mice (<i>P</i> < 0.001), confirming that Notch4 is an important contributor to early pancreatic tumorigenesis.</p><p>To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the PKC and N4<i>⁻^/⁻</i>PKC mice. The N4<i>⁻^/⁻</i>PKC mice had better overall survival (<i>P</i> = 0.012) and significantly reduced tumor burden (PanIN: <i>P</i> = 0.018 at 2 months, PDAC: <i>P</i> = 0.039 at 5 months) compared with the PKC GEMM. RNA-sequencing analysis of pancreatic tumor cell lines derived from the PKC and N4<i>⁻^/⁻</i>PKC GEMMs revealed that 408 genes were differentially expressed (FDR < 0.05) and <i>Pcsk5</i> is a potential downstream effector of the Notch4 signaling pathway (<i>P</i> < 0.001). Low expression of Pcsk5 positively correlates with good survival in patients with PDAC (<i>P</i> = 0.028).</p><p>We have identified a novel role for Notch4 signaling with tumor-promoting function in pancreatic tumorigenesis. Our study also uncovered a novel association between <i>Pcsk5</i> and Notch4 signaling in PDAC.</p>Significance:<p>We demonstrated that global inactivation of <i>Notch4</i> 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.</p></div>