Abstract A059: NF-κB inducing kinase (NIK) deletion accelerates the progression of pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and the leading cause of cancer-related deaths. The canonical NF-κB pathway displays critical functions in the development of PDAC. However, the relationship between the non-canonical NF-κB pathway and PDAC is still obscure. Here, we analyzed the role of the non-canonical NF-κB signaling in precancerous lesions and PDAC development by deleting NF-κB inducing kinase (NIK), an essential kinase for the activation of the non-canonical pathway. We used KC mice (Pdx1-cre/LSL-KrasG12D) that develop pancreatic intraepithelial neoplasias (PanINs) already at the age of 8 weeks. To evaluate the role of the non-canonical NF-κB signaling, KC mice were crossed with NIK-floxed mice (NiC) to generate the KNiC (Pdx1-cre/KRASG12D/NIKfl/fl) mouse model. Mice were injected with cerulein to promote the development of pancreatitis and support the development of PanINs. At the age of 8 weeks, mice were sacrificed and analyzed. Furthermore, to analyze the role of the non-canonical pathway in PDAC development, we crossed -the rapidly PDAC developing- KPC mice (Pdx1-cre/LSL-KrasG12D/p53fl/fl) to NiC mice and generated the KPNiC (Pdx1-cre/KRASG12D/NIKfl/fl/p53fl/fl) mouse model. Mice were analyzed at the age of 8 weeks or when they reached their humane endpoint. Analysis of the pancreata revealed that deletion of NIK supported the development of higher-grade precancerous lesions and an increased remodeling area. Importantly, NIK deletion accelerated the establishment of PDAC already by the age of 8 weeks. In addition, the pancreatic/body weight ratio was significantly higher in the KNiC group compared to the KC group (Mean: KC 0.018 vs KNiC 0.030, P<0.05). These results were further verified by Ki67 staining, where we detected more proliferating cells in KNiC pancreata (Mean: KC 66.53/mm2 vs KNiC 205.60/mm2, P<0.05). Moreover, FN1 expression level (Mean: KC 1.00 vs KNiC 2.14, P<0.05) and the number α-SMA+ cells (Mean: KC 6.73% vs KNiC 17.47%, P<0.05) were dramatically elevated in KNiC pancreata, indicating increased desmoplastic reaction after NIK deletion. Interestingly, KNiC pancreata displayed stronger activation of the STAT3 pathway which is associated with PanIN development and progression (Mean: KC 1.00 vs KNiC 1.73, P<0.05). With respect to the KPC and KPNiC mice, NIK deletion strongly accelerated the development of PDAC at the age of 8 weeks (83.3% of KPNiC mice, 25% of KPC mice). Finally, the median survival of KPNiC mice (71 days) was remarkably shorter than the survival of KPC mice (85 days). Our data demonstrate that deletion of NIK in KC mice promoted the progression of precancerous lesions, a stronger fibrotic reaction, and activation of the STAT3 pathway. Further, deletion of NIK in KPC mice accelerated cancer development and shortened the lifespan of the mice. These results indicate that inactivation of the non-canonical NF-κB pathway leads to PDAC deterioration. Analysis on later time points and further examination of the mechanism is ongoing. Citation Format: Ziwei Du, Miltiadis Tsesmelis, Thomas Wirth. NF-κB inducing kinase (NIK) deletion accelerates the progression of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A059.