Wired to Grow: How Small Cell Lung Cancer Hijacks Neuronal Synapses
An international research team has shown that lung cancer cells can form functional synapses with neurons, effectively hijacking the body’s neural circuits to grow faster. The finding reveals a startling new dimension of cancer biology and opens promising new avenues for therapies against this disease. The study titled “Functional synapses between neurons and small-cell lung cancer” was published in Nature (https://doi.org/10.1038/s41586-025-09434-9).
Previously, synapses had only been seen in brain tumours, which arise from the nervous system itself. Finding that a lung cancer can wire itself into neural circuits reveals how deeply a tumour can integrate with the host to survive and thrive. “Our study underscores the alarming extent to which the organism can communicate with and nurture a tumour, supporting its growth as if it were a healthy tissue,” said Dr. Filippo Beleggia, from the Department of Translational Genomics, who coordinated the study.
Starting from the analysis of genetic data, the researchers identified a set of genes involved in synaptic formation and went on to visualize the presence of synapses between small cell lung cancer (SCLC) cells and neurons in cell culture and in mouse models.
“I was stunned to see the extent of innervation that SCLC cells manage to co-opt,” said senior and co-corresponding author Professor Dr. Matteo Bergami, Principal Investigator at the University of Cologne’s CECAD Cluster of Excellence for Aging Research and at the University´s Center for Molecular Medicine Cologne (CMMC). “I believe that these findings can become transformative for the development of more efficient therapies to prevent SCLC from metastasizing to the brain.”
The researchers detected neuron-to-cancer synaptic communication through two different neurotransmitters: glutamate and GABA. They further found that SCLC cells proliferated faster in the presence of sensory or cortical neurons.
“By forming synaptic connections with different types of neurons, SCLC cells reveal an impressive adaptability to boost their growth,” said Dr. Elisa Motori from the Institute of Biochemistry and associated to the University´s Center of Molecular Medicine Cologne (CMMC), who is one one of the senior and co-corresponding authors. “It is tempting to speculate that SCLC cells are not only ‘chatting’ with neurons but are also receiving resources from them to support their growth.”
Crucially, disrupting glutamate signalling led to lower tumour burden and longer survival of the experimental mice, highlighting promising new targets for cancer therapy. “Our observations may open a path forward for the implementation of novel therapeutic interventions in SCLC,” said lead corresponding author Professor Dr. Christian Reinhardt from the West German Cancer Center at the University Hospital Essen. “We have shown that pharmacological disruption of the cancer–neuron crosstalk leads to improved tumour control and that such treatments can be combined with chemotherapy.”
The large international collaboration was led by the laboratories of
Dr Filippo Beleggia (University of Cologne)
Prof. Dr Christian Reinhardt (University Hospital Essen)
Dr Elisa Motori (University of Cologne)
Prof. Dr Matteo Bergami (University of Cologne)
Prof. Dr Silvio Rizzoli (University of Göttingen)
Prof. Dr Max Anstötz (Heinrich Heine University Düsseldorf)
with key partners in Cologne, Munich,Antwerp and Stanford
These discoveries suggest several therapeutic possibilities, from repurposing existing neurotransmitter-blocking drugs to developing entirely new approaches targeting cancer–neuron communication. The research team continues to investigate the molecular details of these synaptic connections, work that will be essential for optimizing treatment strategies and identifying the most promising therapeutic combinations.
The research was primarily supported by the German Cancer Aid (Deutsche Krebshilfe) and by the German Research Foundation (DFG) through Collaborative Research Centre 1399 – Mechanisms of Drug Sensitivity and Resistance in Small Cell Lung Cancer. The project also received generous support from a wide range of national and international funding agencies, including the Boehringer Ingelheim Stiftung. A full list is available in the published paper.
“Who are Elisa Motori and Matteo Bergami? - Learn more about their research activities
Original Publication
https://www.nature.com/articles/s41586-025-09434-9
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 Ianicelli 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*
Functional synapses between neurons and small cell lung cancer. Nature (2025). https://doi.org/10.1038/s41586-025-09434-9
Authors with CMMC affiliation indicated in bold and leading authors with a star (*) .
Scientific Contact:
Dr Filippo Beleggia
filippo.beleggia[at]uk-koeln.de
Dr Elisa Motori
elisa.motori[at]uni-koeln.de
This message has been modified by the CMMC (K. Heber & D. Grosskopf-Kroiher) and is based on the text by the press and communications team of the University of Cologne (Anna Euteneuer, responsible Dr. Elisabeth Hoffmann – e.hoffmann@verw.uni-koeln.de, original version here).