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Functional synapses between neurons and small cell lung cancer.
Vignesh Sakthivelu1,2,3, Anna Schmitt2,4, Franka Odenthal5
1Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Nature
|September 10, 2025
Summary
Small cell lung cancer (SCLC) cells form functional synapses with neurons, receiving synaptic inputs. This interaction promotes SCLC proliferation, suggesting glutamate signaling inhibition as a therapeutic strategy.
Area of Science:
- Oncology
- Neuroscience
- Cancer Biology
Background:
- Small cell lung cancer (SCLC) is aggressive with high mortality.
- Innervation plays a role in cancer development and progression.
- Cancer-to-neuron synapses are known in gliomas, but not peripheral tumors.
Purpose of the Study:
- Investigate if SCLC cells can form functional synapses with neurons.
- Determine the role of neuron-SCLC interactions in tumor growth.
- Explore therapeutic interventions targeting these interactions.
Main Methods:
- In vivo insertional mutagenesis screening.
- Cross-species genomic and transcriptomic validation.
- In vitro and in vivo co-culture experiments with neurons.
- Electrophysiology and optogenetic analyses.
- Autochthonous mouse model of SCLC.
Main Results:
- SCLC cells form functional synapses and receive synaptic transmission from neurons.
- Identified neuronal, synaptic, and glutamatergic signaling gene sets in SCLC.
- SCLC cells demonstrated a proliferation advantage when co-cultured with neurons.
- Inhibition of glutamate signaling showed therapeutic efficacy in a mouse model.
Conclusions:
- SCLC cells hijack synaptic signaling pathways for tumor growth.
- Neuron-SCLC interactions represent a novel therapeutic target.
- Targeting glutamate signaling offers a potential treatment strategy for SCLC.
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