Constitutive non-canonical NF-kappaB signaling in pancreatic cancer

The NF-kappaB signaling pathway regulates the expression of genes critical to the immune response, inflammation, and cell survival, and constitutive activation of this pathway has been associated with dozens of human cancers. Correspondingly, suppression of NF-kappaB signaling is under intense scrutiny for potential clinical applications. However, the majority of studies regarding the contribution of NF-kappaB signaling to tumorigenesis examine only classical NF-kappaB signaling. The more recently described non-canonical NF-kappaB pathway has not been specifically investigated for its role in cancer development. The non-canonical pathway is IKKalpha-dependent, and is characterized by stabilization of the protein NIK and processing of NF-kappaB2/p100 to p52. Target genes of this pathway include the cytokine BAFF and the chemokines CXCL12, CXCL13, CCL19, and CCL21. These proteins function in lymphoid development, immune cell trafficking, and angiogenesis. Several of them have been observed in association with both lymphoid malignancies and solid tumors. We investigated the activation state of the non-canonical NF-kappaB pathway and its target genes in pancreatic ductal adenocarcinoma (PDAC), and found this pathway to be constitutively activated. The NC NF-kappaB proteins p52 and RelB were expressed in the nuclei of human pancreatic tumor tissues and PDAC cell lines. Additionally, the panel of PDAC cell lines exhibited NC activation in terms of modification and processing of p100 and stabilization of NIK. Strikingly, these cells also dramatically overexpressed NC NF-kappaB target genes. We confirmed the role of NC activation in the upregulation of these genes by inhibiting NC signaling and suppressing the expression of these chemokines and cytokines. We also found that PDAC cells release soluble factors that stimulate expression of NC target genes in endothelium, indicating a critical role for NC NF-kappaB signaling in the tumor microenvironment. These observations demonstrate that the NC NF-kappaB pathway is constitutively activated in PDAC cells, and these findings strongly suggest a functional role for this pathway in tumorigenesis.