Molecular taxonomy of pancreatic neuroendocrine tumors reveals BEND2-fusions-driven transcriptional plasticity and therapeutic vulnerabilities - PubMed
4 days ago
- #pancreatic neuroendocrine tumors
- #transcriptional reprogramming
- #BEND2 fusions
- Pancreatic neuroendocrine tumors (pNETs) exhibit substantial clinical and molecular heterogeneity.
- Five molecular subtypes identified: Hedgehog-high, Alpha-like, Hypoxia-high, Gastrin-high, and Progenitor-like.
- 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.
- 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 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.
- Findings define a molecular taxonomy of pNETs and nominate tumor-intrinsic and microenvironmental programs as actionable targets.