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2025
Nature
Functional synapses between neurons and small cell lung cancer
Authors:
Vignesh Sakthivelu, Anna Schmitt, Franka Odenthal, Kristiano Ndoci, Marian Touet, Ali H. Shaib, Abdulla Chihab, Gulzar A. Wani, Pascal Nieper, Griffin G. Hartmann, Isabel Pintelon, Ilmars Kisis, Maike Boecker, Naja M. Eckert, Manoela Iannicelli Caiaffa, Olta Ibruli, Julia Weber, Roman Maresch, Christina M. Bebber, Ali Chitsaz, Anna Lütz, Mira Kim Alves Carpinteiro, Kaylee M. Morris, Camilla A. Franchino, Jonas Benz, Laura Pérez-Revuelta, Jorge A. Soriano-Campos, Maxim A. Huetzen, Jonas Goergens, Milica Jevtic, Hannah M. Jahn-Kelleter, Hans Zempel, Aleksandra Placzek, Alexandru A. Hennrich, Karl-Klaus Conzelmann, Hannah L. Tumbrink, Pascal Hunold, Joerg Isensee, Lisa Werr, Felix Gaedke, Astrid Schauss, Marielle Minère, Marie Müller, Henning Fenselau, Yin Liu, Alena Heimsoeth, Gülce S. Gülcüler Balta, Henning Walczak, Christian Frezza, Ron D. Jachimowicz, Julie George, Marcel Schmiel, Johannes Brägelmann, Tim Hucho, Silvia von Karstedt, Martin Peifer, Alessandro Annibaldi, Robert Hänsel-Hertsch, Thorsten Persigehl, Holger Grüll, Martin L. Sos, Guido Reifenberger, Matthias Fischer, Dirk Adriaensen, Reinhard Büttner, Julien Sage, Inge Brouns, Roland Rad, Roman K. Thomas, Max Anstötz, Silvio O. Rizzoli, Matteo Bergami, Elisa Motori, Hans Christian Reinhardt, Filippo Beleggia
Keywords:
Small cell lung cancer; SCLC; Cancer genomics; Cancer microenvironment; Cancer-to-neuron synapse; innervation; oncogenic; synaptic signalling
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 rate1,2,3. Recent evidence has suggested that innervation has an important role in the development and progression of several types of cancer4,5. Cancer-to-neuron synapses have been reported in gliomas6,7, 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 GABAA 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.