Cell state programs offer a potential axis for classifying neuroendocrine tumors.

Neuronal-like and secretory neuroendocrine malignant cell states were identified across 38 pancreatic and small-intestinal GEP-NETs, revealing a conserved cell-state axis.

• Why it matters: Current GEP-NET classification by site, morphology, and proliferation indices leaves limited prognostic resolution and restricts more personalized treatment decisions.
• What they did: Karam, Hoffman, and colleagues used joint single-nucleus RNA and ATAC sequencing on 38 pancreatic and small-intestinal NETs, then projected malignant cell-associated programs onto matched spatial transcriptomes.
• The result: The two malignant states span a continuum across organ sites, show distinct transcription factor motif enrichment and microenvironmental niches, and secretory program scores trend higher in metastatic disease, suggesting prognostic value.

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