Xiaofan Lu, Philippe Baltzinger, Li Xu, Antonin Fattori, Sehrish Khan Bazai, Fatima Alhourani, Marie-Pierrette Chenard, Philippe Bachellier, Pietro Addeo, Véronique Debien, Clara Vacheret, Alessio Imperiale, Patrick Pessaux, Wenxuan Cheng, Martin Balzinger, J.E. Kurtz, Irwin Davidson, Xiaoping Su, Bernard Goichot, Gabriel G. Malouf
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.