Julia Scott¹, Natalie Kavaler¹, Bim de Klein¹, Catrin Lutz², Emmanouela Epeslidou¹, Theofilos Chalkiadakis¹, Stefan Prekovic¹

(1) Centre for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.

(2) Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Intra-tumor heterogeneity, fueled by lineage plasticity and cellular state transitions, is a critical driver of therapeutic resistance. The development of neuroendocrine neoplasms (NENs) exemplifies this challenge, yet the shared molecular programs driving their malignancy remain undefined at single-cell resolution. To address this problem, we established the first pan-NEN single-cell RNA sequencing atlas by integrating approximately 300,000 cells from 14 studies across seven diverse anatomical sites. Leveraging a metaprogram-based analysis, we aimed to define the conserved transcriptional architecture of NEN malignancies. This unbiased approach identified two novel, previously uncharacterized neuroendocrine metaprograms (a neuronal development NE-MP4 and a metabolic NE-MP6) that are conserved across primary NEN sites. Subsequent validation in an independent TCGA cohort confirmed the upregulation of these novel metaprograms among neuroendocrine-like malignancies, supporting their relevance in a larger cohort. Critically, gene dependency analysis pinpointed the transcription factor SOX11 as a key dependency and candidate master regulator driving the NE-MP4-defined neuroendocrine-like phenotype across all sites analyzed. By nominating SOX11 as a central regulator of a shared neuroendocrine identity, this study offers preliminary mechanistic insight into regulation of lineage plasticity in NENs and identifies a novel, conserved potential therapeutic target for intervention across the spectrum of neuroendocrine cancers.