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

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.