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Publication : Functional synapses between neurons and small cell lung cancer.

First Author  Sakthivelu V Year  2025
Journal  Nature Volume  646
Issue  8087 Pages  1243-1253
PubMed ID  40931078 Mgi Jnum  J:378216
Mgi Id  MGI:8273451 Doi  10.1038/s41586-025-09434-9
Citation  Sakthivelu V, et al. (2025) Functional synapses between neurons and small cell lung cancer. Nature 646(8087):1243-1253
abstractText  Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, frequent early relapse and a high mortality rate(1-3). Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer(4,5). Cancer-to-neuron synapses have been reported in gliomas(6,7), but whether peripheral tumours can form such structures is unknown. Here we show that SCLC cells can form functional synapses and receive synaptic transmission. Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified neuronal, synaptic and glutamatergic signalling gene sets in mouse and human SCLC. Further experiments revealed the ability of SCLC cells to form synaptic structures with neurons in vitro and in vivo. Electrophysiology and optogenetic experiments confirmed that cancer cells can receive NMDA receptor- and GABA(A) receptor-mediated synaptic inputs. Fitting with a potential oncogenic role of neuron-SCLC interactions, we showed that SCLC cells derive a proliferation advantage when co-cultured with vagal sensory or cortical neurons. Moreover, inhibition of glutamate signalling had therapeutic efficacy in an autochthonous mouse model of SCLC. Therefore, following malignant transformation, SCLC cells seem to hijack synaptic signalling to promote tumour growth, thereby exposing a new route for therapeutic intervention.
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