Effect of the depletion of NR4A1 on gene expression in PNET cell line QGP-1

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 as an oncogenic driver in PNETs, regulated through both cancer cell extrinsic and intrinsic mechanisms.

CellChat analysis revealed M2-like tumour-associated macrophages as the dominant source of NF-κB-activating cytokines within the PNET microenvironment. Concurrently, we uncover a cancer cell intrinsic safeguard mechanism wherein the tumour suppressor menin associates with RelA to suppress PNET growth. Molecular docking identified key residues mediating the menin-RelA interaction and revealed three clinically relevant menin mutants (P320R, R415P, W423R) that destabilize this complex, thereby compromising menin’s ability to suppress PNET growth.