Menin-RelA complex antagonizes cancer cell-intrinsic and tumor microenvironment-induced NF-κB hyperactivation to suppress pancreatic neuroendocrine tumorigenesis

Pancreatic neuroendocrine tumors (PNETs) are rare neuroendocrine cancers with high mortality rates and an immense unmet medical need. While the genetic and immune landscape of PNETs is defined, the molecular mechanisms linking these factors to tumorigenesis remain poorly understood. Here, we identify NF-κB signaling as a key effector pathway that contributes to PNET tumorigenesis, regulated through both cancer cell extrinsic and intrinsic mechanisms. CellChat analysis identifies M2-like macrophages as the dominant source of NF-κB-activating cytokines, and co-culture of PNET cancer cells with THP-1-derived M2-macrophages significantly enhances RelA phosphorylation and colony-forming capacity in vitro. Concurrently, we uncovered a cancer cell intrinsic safeguard mechanism wherein the tumor suppressor menin physically associates with RelA to suppress PNET growth in vitro and in vivo. Molecular docking identified key residues mediating the menin-RelA interaction and revealed three clinically relevant menin mutants (P320R, R415P, W423R) that destabilize this complex, compromising menin’s ability to restrain PNET growth. Mechanistically, menin and RelA co-bind κB sites on promoters of proliferation-associated NF-κB target genes, including NR4A1, and epigenetically silence their expression through reduced H3K27ac. Crucially, NR4A1 depletion or small-molecule inhibition suppresses PNET growth in vitro and in vivo. Together, our findings reveal a novel menin-RelA-NR4A1 axis that regulates PNET growth and demonstrates how extrinsic and intrinsic factors converge on NF-κB signaling, highlighting potential therapeutic avenues.