Functional synapses between neurons and small cell lung cancer

Nature. 2025 Sep 10. doi: 10.1038/s41586-025-09434-9.

Vignesh Sakthivelu ^# ¹ ² ³, Anna Schmitt ^# ² ⁴, Franka Odenthal ^# ⁵, Kristiano Ndoci ^# ⁶, Marian Touet ^# ² ⁷, Ali H Shaib ^# ⁸, Abdulla Chihab ^# ⁶, Gulzar A Wani ⁶, Pascal Nieper ¹ ², Griffin G Hartmann ⁹ ¹⁰, Isabel Pintelon ¹¹ ¹², Ilmars Kisis ¹ ² ³, Maike Boecker ¹ ² ³, Naja M Eckert ¹, Manoela Iannicelli Caiaffa ¹ ² ³, Olta Ibruli ¹ ², Julia Weber ¹³, Roman Maresch ¹³, Christina M Bebber ¹ ⁶, Ali Chitsaz ¹ ² ³, Anna Lütz ¹ ² ³, Mira Kim Alves Carpinteiro ¹ ² ³, Kaylee M Morris ⁵, Camilla A Franchino ⁵, Jonas Benz ⁶, Laura Pérez-Revuelta ⁶, Jorge A Soriano-Campos ⁶, Maxim A Huetzen ² ⁶ ¹⁴ ¹⁵, Jonas Goergens ² ⁶ ¹⁴ ¹⁵, Milica Jevtic ⁶, Hannah M Jahn-Kelleter ⁶, Hans Zempel ¹⁵ ¹⁶, Aleksandra Placzek ⁶, Alexandru A Hennrich ¹⁷, Karl-Klaus Conzelmann ¹⁷, Hannah L Tumbrink ¹ ¹⁸, Pascal Hunold ¹ ¹⁵, Joerg Isensee ¹⁹ ²⁰, Lisa Werr ²¹, Felix Gaedke ⁶, Astrid Schauss ⁶, Marielle Minère ⁶ ²², Marie Müller ⁶ ²², Henning Fenselau ⁶ ²² ²³, Yin Liu ²⁴, Alena Heimsoeth ¹ ¹⁵ ¹⁸, Gülce S Gülcüler Balta ¹ ² ³, Henning Walczak ⁶ ²⁵ ²⁶, Christian Frezza ²⁷ ²⁸, Ron D Jachimowicz ² ⁶ ¹⁴ ¹⁵, Julie George ¹ ²⁹, Marcel Schmiel ³⁰, Johannes Brägelmann ¹ ³ ¹⁵, Tim Hucho ¹⁹ ²⁰, Silvia von Karstedt ¹ ⁶ ¹⁵, Martin Peifer ¹ ¹⁵, Alessandro Annibaldi ¹⁵, Robert Hänsel-Hertsch ¹ ⁶ ¹⁵ ¹⁶, Thorsten Persigehl ³¹, Holger Grüll ³¹, Martin L Sos ¹ ³² ³³, Guido Reifenberger ³⁴, Matthias Fischer ¹⁵ ²¹, Dirk Adriaensen ¹¹, Reinhard Büttner ³⁰, Julien Sage ⁹ ¹⁰, Inge Brouns ¹¹, Roland Rad ¹³, Roman K Thomas ¹ ³⁰, Max Anstötz ³⁵, Silvio O Rizzoli ³⁶ ³⁷ ³⁸, Matteo Bergami ³⁹ ⁴⁰ ⁴¹ ⁴², Elisa Motori ⁴³ ⁴⁴ ⁴⁵, Hans Christian Reinhardt ⁴⁶ ⁴⁷ ⁴⁸ ⁴⁹, Filippo Beleggia ⁵⁰ ⁵¹ ⁵²

Affiliations

1 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
2 Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
3 Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
4 Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
5 Institute of Biochemistry, University of Cologne, Cologne, Germany.
6 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
7 Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany.
8 Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany.
9 Department of Pediatrics, Stanford University, Stanford, CA, USA.
10 Department of Genetics, Stanford University, Stanford, CA, USA.
11 Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
12 Antwerp Centre for Advanced Microscopy (ACAM), University of Antwerp, Antwerp, Belgium.
13 Institute of Molecular Oncology and Functional Genomics, School of Medicine, Technical University of Munich, Munich, Germany.
14 Max Planck Institute for Biology of Ageing, Cologne, Germany.
15 Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
16 Institute of Human Genetics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
17 Virology, Max von Pettenkofer Institute, Faculty of Medicine and Gene Center, Ludwig Maximilians University, Munich, Germany.
18 Molecular Pathology, Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
19 Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
20 Pain Center, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
21 Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
22 Research Group Synaptic Transmission in Energy Homeostasis, Max Planck Institute for Metabolism Research, Cologne, Germany.
23 Policlinic for Endocrinology, Diabetes and Preventive Medicine, University Hospital Cologne, Cologne, Germany.
24 Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
25 Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Center for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
26 Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK.
27 Institute for Metabolomics in Ageing, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
28 Institute of Genetics, University of Cologne, Faculty of Mathematics and Natural Sciences, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany.
29 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Cologne, Cologne, Germany.
30 Institute of Pathology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
31 Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
32 Department of Translational Oncology, German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and Ludwig-Maximilians-Universität München (LMU), Munich, Germany.
33 Department of Medicine III, LMU University Hospital Munich, Munich, Germany.
34 Institute of Neuropathology, Medical Faculty, Heinrich Heine University and University Hospital Düsseldorf, Düsseldorf, Germany.
35 Institute of Anatomy II, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany. max.anstoetz@hhu.de.
36 Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, Germany. srizzol@gwdg.de.
37 Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany. srizzol@gwdg.de.
38 Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Göttingen, Germany. srizzol@gwdg.de.
39 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. matteo.bergami@uk-koeln.de.
40 Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. matteo.bergami@uk-koeln.de.
41 Institute of Genetics, University of Cologne, Cologne, Germany. matteo.bergami@uk-koeln.de.
42 Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. matteo.bergami@uk-koeln.de.
43 Institute of Biochemistry, University of Cologne, Cologne, Germany. elisa.motori@uni-koeln.de.
44 Cologne Excellence Cluster on Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany. elisa.motori@uni-koeln.de.
45 Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. elisa.motori@uni-koeln.de.
46 Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany. christian.reinhardt@uk-essen.de.
47 West German Cancer Center, University Hospital Essen, Essen, Germany. christian.reinhardt@uk-essen.de.
48 DKTK, partner site Essen, University Hospital Essen, Essen, Germany. christian.reinhardt@uk-essen.de.
49 Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany. christian.reinhardt@uk-essen.de.
50 Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. filippo.beleggia@uk-koeln.de.
51 Department I of Internal Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. filippo.beleggia@uk-koeln.de.
52 Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. filippo.beleggia@uk-koeln.de.
# Contributed equally.

PMID: 40931078 DOI: 10.1038/s41586-025-09434-9

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^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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