Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer marked by dense stroma, immune suppression, and therapy resistance. While canonical NF-κB signaling has been extensively studied in PDAC, the non-canonical pathway and its key kinase, NF-κB–inducing kinase (NIK), remain less characterized. Here, we employed genetically engineered mouse models, including Pdx1-Cre; KRAS G12D (KC), Pdx1-Cre; KRAS G12D ; p53 fl/fl (KPC), and their NIK-deficient counterparts (KNiC and KPNiC). To mimic inflammation-driven tumorigenesis observed in human PDAC, we administered cerulein in the KC and KNiC mice to induce pancreatitis and promote lesion progression. We found that NIK deletion accelerated lesion formation, progression to high-grade PanINs and invasive carcinoma in both KC and KPC backgrounds. Despite similar tumor grade and burden at endpoint, KPNiC mice exhibited shortened survival compared to controls, indicating that NIK acts as a tumor-suppressor and limits early-stage tumor progression. Mechanistically, NIK loss was associated with elevated ERK signaling that increased lesion cell proliferation, and also reduced acinar cell death following pancreatitis. In the tumor microenvironment, NIK deletion promoted myofibroblast activation and enrichment of myCAF-associated gene expression, likely through secondary activation of canonical NF-κB and pro-fibrotic signaling pathways such as TGF-β, Wnt, and FGF. Finally, increased IL6–STAT3 signaling and neutrophil infiltration were observed, suggesting broader immunostromal remodeling in the absence of NIK. Consistent with these findings, analysis of TCGA-PAAD data showed that low NIK expression correlates with poor overall survival in human PDAC. These findings reveal a tumor-suppressive role of NIK in pancreatic cancer and underscore the need for caution in targeting NF-κB signaling, as balanced pathway activity appears critical for regulating early tumor progression and microenvironmental interactions in PDAC.
Du et al. (Wed,) studied this question.