Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA sequencing.

Small-cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy in which neural activity is implicated in tumor progression. Nevertheless, whether primary SCLC elicits systemic effects on the brain remains uncertain. Using an Rb1/Trp53/Myc-driven SCLC mouse model, we performed whole-brain single-nucleus RNA sequencing (n = 48,686 nuclei) integrated with transcriptomic and metabolomic analyses of lung tumors and plasma, validating our findings across public SCLC cohorts. Pharmacological inhibition of GABAA receptors with flumazenil was also applied in vivo. We observed widespread, cell-type-resolved transcriptional alterations across the brain in tumor-bearing mice. Gad2 expression broadly increased in basal ganglia cells and GABAergic inhibitory neurons. Concurrently, oligodendrocyte precursor cells exhibited impaired maturation, accompanied by coordinated downregulation of myelination-related genes (Mbp, Plp1, Mobp). Metabolomic analyses demonstrated significantly higher levels of glutamate and GABA in lung tumors from tumor-bearing mice relative to sham-treated controls. Clinical measurements indicated that glutamate and GABA were markedly increased in SCLC patient plasma, suggesting a systemic elevation of these neurotransmitters associated with tumor progression. Furthermore, pharmacological inhibition of GABAA receptors with flumazenil significantly suppressed tumor growth in vivo. Primary SCLC is associated with cell-type-specific brain transcriptional remodeling and elevated circulating glutamate, providing descriptive evidence for a lung-brain metabolic axis. However, direct causal links within this axis remain to be established through future interventional studies.