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

Background 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. Methods 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 GABA A receptors with flumazenil was also applied in vivo . Results 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 GABA A receptors with flumazenil significantly suppressed tumor growth in vivo . Conclusions 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.