Immunosuppressive myeloid signaling and distinct malignant cell states in pancreatic neuroendocrine tumors revealed by single-nucleus RNA-seq

Pancreatic neuroendocrine tumors (PNET) are rare and heterogeneous neoplasms with increasing incidence worldwide. Currently, there is no clinically-relevant molecular framework for risk-stratifying patients with PNET. In this study, we used single-nucleus RNA-sequencing to uncover the spectrum of malignant cell states and interactions within the tumor microenvironment. We uncovered a gene expression program enriched in neural/synaptic signaling genes associated with aggressive clinical behavior, altered telomeres, and broad chromosomal loss of heterozygosity. Moreover, it is associated with worse overall survival in independent cohorts. Another novel malignant cell state was enriched for VEGF-signaling and found to interact with macrophages via glutamate, promoting an immunosuppressive phenotype in macrophages and a more invasive phenotype in malignant cells. This study provides insight into the heterogeneity of malignant cells in PNET, and these diverse cell states and intercellular interactions that may be further explored for prognostication and therapeutic targeting.