Functional synapses between neurons and small cell lung cancer

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<sup>1-3</sup>. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer<sup>4,5</sup>. Cancer-to-neuron synapses have been reported in gliomas<sup>6,7</sup>, 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<sub>A</sub> 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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Journal
Nature
Published
2025-09-10
DOI
https://doi.org/10.1038/s41586-025-09434-9
Citations
21
Primary Topic
Lung Cancer Research Studies
Type
article
Field-Weighted Citation Impact
21.95
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article

Functional synapses between neurons and small cell lung cancer

Matteo Bergami, Reinhard Büttner, Isabel Pintelon, Laura Pérez-Revuelta et al.
21 citations
Nature
Lung Cancer Research Studies
21.95
article

Functional synapses between neurons and small cell lung cancer

Matteo Bergami, Reinhard Büttner, Isabel Pintelon, Laura Pérez-Revuelta, Christian Frezza, Guido Reifenberger, Thorsten Persigehl, Robert Hänsel‐Hertsch, Felix Gaedke, Jonas Goergens, Inge Brouns, Karl‐Klaus Conzelmann, Ilmars Kisis, Astrid Schauß, Alexandru A. Hennrich, Gülce S. Gülcüler Balta, Ron D. Jachimowicz, Hans Christian Reinhardt, Roman Maresch, Jörg Isensee, Silvia von Karstedt, Marian Touet, Gulzar A. Wani, Alena Heimsoeth, Aleksandra Placzek, Maxim A. Huetzen, Hannah L. Tumbrink, Filippo Beleggia, Olta Ibruli, Yin Liu, Dirk Adriaensen, Lisa Werr, Maike Boecker, Kristiano Ndoci, Ali Shaib, Pascal Nieper, Franka Odenthal, Alessandro Annibaldi, Christina M. Bebber, Martin L. Sos, Marcel Schmiel, Roman Kurt Thomas, Milica Jevtic, Elisa Motori, Marielle Minère, Silvio O. Rizzoli, Matthias Fischer, Julia Weber, Vignesh Sakthivelu, Holger Grüll, Martin Peifer, Griffin G. Hartmann, Julien Sage, Max Anstötz, Anna Schmitt, Henning Fenselau, Roland Rad, Henning Walczak, Ahmad Chitsaz, Pascal Hunold, Johannes Brägelmann, Hans Zempel, Tim Hucho, Anna Lütz, Camilla Aurora Franchino, Hannah M. Jahn-Kelleter, Julie George, Marie Müller, Kathleen Morris, Abdulla Chihab, Naja Maria Eckert, Manoela Iannicelli Caiaffa, Mira Kim Alves Carpinteiro, Jonas Benz, Jorge A. Soriano-Campos
article en
21 citations

Abstract

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<sup>1-3</sup>. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer<sup>4,5</sup>. Cancer-to-neuron synapses have been reported in gliomas<sup>6,7</sup>, 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<sub>A</sub> 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.

NatureVol. 646(8087)
TH Köln - University of Applied Sciences (DE), Howard Hughes Medical Institute (US), University of Antwerp (BE), University of Cologne (DE), Janelia Research Campus (US), LMU Klinikum (DE), Düsseldorf University Hospital (DE), Max Planck Institute for Metabolism Research (DE), Universitätsmedizin Göttingen (DE), Essen University Hospital (DE), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), CRUK Lung Cancer Centre of Excellence (GB), Verbundzentrale des GBV (DE), University Hospital Cologne (DE), Max Planck Institute for Biology of Ageing (DE), West German Heart and Vascular Center Essen (DE), Heinrich Heine University Düsseldorf (DE), University College London (GB), Technical University of Munich (DE), University of Göttingen (DE), Ludwig-Maximilians-Universität München (DE), Stanford University (US)
Openalex Percentile: Top 0%
Lung Cancer Research Studies
21.95
DOIOpen Access PDFOpenAlex
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