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

Fiche publication

Date publication

mars 2026

Journal

Cell reports. Medicine

Auteurs

Membres identifiés du Cancéropôle Est :
Pr BACHELLIER Philippe , Pr CHENARD Marie-Pierre , Dr DAVIDSON Irwin , Pr KURTZ Jean-Emmanuel , Pr PESSAUX Patrick , Pr MALOUF Gabriel , Pr IMPERIALE Alessio , Dr BALTZINGER Philippe

Tous les auteurs :
Lu X, Baltzinger P, Xu L, Fattori A, Bazai SK, Alhourani F, Chenard MP, Bachellier P, Addeo P, Debien V, Vacheret C, Imperiale A, Pessaux P, Cheng W, Balzinger M, Kurtz JE, Davidson I, Su X, Goichot B, Malouf GG

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/41794038

Résumé

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.