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

## TL;DR

This study identifies a new aggressive subtype of pancreatic neuroendocrine tumors driven by BEND2 gene fusions, offering potential new treatment strategies.

## Contribution

The discovery of BEND2 fusions as a driver of transcriptional plasticity in a clinically aggressive pNET subtype.

## Key findings

- BEND2 fusions occur in 5% of pNETs and define the Gastrin-high subtype with poor outcomes.
- BEND2 fusions reprogram cells toward mesenchymal and immune-related states.
- NOTCH3 signaling and immune checkpoint pathways suggest therapeutic vulnerabilities.

## Abstract

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.

•BEND2 gene fusions define a clinically aggressive Gastrin-high subtype of pNETs•BEND2 fusions are mutually exclusive from MEN1, DAXX, and ATRX mutations•BEND2 fusions reprogram neuroendocrine cells toward mesenchymal and inflamed states•Chromatin and immune programs nominate therapeutic targets in BEND2-fusion tumors

BEND2 gene fusions define a clinically aggressive Gastrin-high subtype of pNETs

BEND2 fusions are mutually exclusive from MEN1, DAXX, and ATRX mutations

BEND2 fusions reprogram neuroendocrine cells toward mesenchymal and inflamed states

Chromatin and immune programs nominate therapeutic targets in BEND2-fusion tumors

Lu et al. identify BEND2 fusions in ∼5% of pancreatic neuroendocrine tumors, defining an aggressive Gastrin-high subtype. Integrating bulk and single-nucleus RNA sequencing with functional assays, BEND2 fusions are shown to drive transcriptional plasticity and nominate chromatin and immune signaling programs as actionable therapeutic targets.