Molecular taxonomy of pancreatic neuroendocrine tumors reveals BEND2-fusions-driven transcriptional plasticity and therapeutic vulnerabilities.

Pancreatic neuroendocrine tumors (pNETs) exhibit substantial clinical and molecular heterogeneity. Using bulk and single-nucleus RNA sequencing, we identify five molecular subtypes: Hedgehog-high, Alpha-like, Hypoxia-high, Gastrin-high, and Progenitor-like. The Gastrin-high and Progenitor-like subtypes associate with poor clinical outcomes. BEND2 gene fusions occur in 5% of pNETs, all belonging to the Gastrin-high subtype, which shows activation of the late endocrine progenitor FEV regulon. Functional studies in pNET cell models demonstrate that BEND2 fusions drive transcriptional reprogramming, promoting a shift from ASCL1(+) endocrine states toward neurodevelopmental, mesenchymal, and immune-related gene programs. Single-nucleus analysis reveals complex multicellular ecosystems, with NOTCH3-mediated signaling between tumor cells and myofibroblasts emerging as a potential therapeutic vulnerability. Gastrin-high tumors exhibit CD8(+) T cell infiltration alongside PD-1/PD-L1 upregulation, suggesting potential responsiveness to immune checkpoint blockade. These findings define a molecular taxonomy of pNETs and nominate tumor-intrinsic and microenvironmental programs as actionable targets.