Epigenetic Context Defines the Transcriptional Activity of Canonical and Noncanonical NF-kappaB Signaling in Pancreatic Cancer [ChIP-Seq]

NF-κB signaling in pancreatic ductal adenocarcinoma (PDAC) operates through canonical and noncanonical pathways mediated by RELA and RELB, respectively. We show that TNFα selectively activates the canonical RELA pathway, while TWEAK induces noncanonical signaling through RELB. Through integrated transcriptomic, epigenomic, and transcription factor binding analyses, we reveal distinct temporal dynamics and binding patterns, with RELB preferentially occupying AP1-rich, epigenetically active regions. Single-cell RNA-seq and tissue staining highlight pathway-specific crosstalk with the tumor microenvironment. These findings uncover fundamental differences in RELA and RELB regulatory mechanisms and their distinct contributions to PDAC gene regulation.