Critical changes in whole-brain gene networks in response to small-cell lung cancer as revealed by single-nucleus RNA
Jingwei Duan1,2, Qi Fu1, Yongkun Huo1
1Key Laboratory of Brain, Cognition and Education Sciences, Ministry of Education, Institute for Brain Research and Rehabilitation, and Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, Guangdong, China.
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 GABAA 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 GABAA 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.
Insights
Primary small-cell lung cancer (SCLC) alters brain cell activity and neurotransmitter levels. Targeting GABA receptors with flumazenil suppressed tumor growth in mice, suggesting a lung-brain metabolic axis.
Area of Science:
- Neuroscience
- Oncology
- Metabolomics
Background:
- Small-cell lung cancer (SCLC) is an aggressive neuroendocrine cancer.
- Neural activity is linked to SCLC progression.
- Systemic effects of SCLC on the brain are not well understood.
Purpose of the Study:
- Investigate the systemic effects of primary SCLC on the brain.
- Identify molecular and metabolic changes in the brain associated with SCLC.
- Explore potential therapeutic targets within the identified pathways.
Main Methods:
- Utilized a genetically engineered SCLC mouse model (Rb1/Trp53/Myc).
- Performed whole-brain single-nucleus RNA sequencing, transcriptomic, and metabolomic analyses.
- Validated findings in public SCLC patient cohorts and used flumazenil to inhibit GABA receptors in vivo.
Main Results:
- Observed widespread, cell-type-specific transcriptional changes in the brain of tumor-bearing mice.
- Noted increased Gad2 expression in basal ganglia and GABAergic neurons, with impaired oligodendrocyte maturation.
- Found elevated glutamate and GABA in SCLC tumors and patient plasma, and flumazenil suppressed tumor growth.
Conclusions:
- Primary SCLC induces cell-type-specific brain transcriptional remodeling.
- Elevated circulating glutamate suggests a lung-brain metabolic axis.
- Further interventional studies are needed to establish direct causal links.
