Functional synapses between neurons and small cell lung cancer

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 Wani⁶, 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 Eckert¹, Manoela Iannicelli Caiaffa^{1

2

3}, Olta Ibruli^{1

2}, Julia Weber¹³, Roman Maresch¹³, Christina M Bebber^{1

6}, Ali Chitsaz^{1

2

3}, Anna Lütz^{1

2

3}, Mira Kim Alves Carpinteiro^{1

2

3}, Kaylee M Morris⁵, Camilla A Franchino⁵, Jonas Benz⁶, Laura Pérez-Revuelta⁶, Jorge A Soriano-Campos⁶, Maxim A Huetzen^{2

6

14

15}, Jonas Goergens^{2

6

14

15}, Milica Jevtic⁶, Hannah M Jahn-Kelleter⁶, Hans Zempel^{15

16}, Aleksandra Placzek⁶, Alexandru A Hennrich¹⁷, Karl-Klaus Conzelmann¹⁷, Hannah L Tumbrink^{1

18}, Pascal Hunold^{1

15}, Joerg Isensee^{19

20}, Lisa Werr²¹, Felix Gaedke⁶, Astrid Schauss⁶, Marielle Minère^{6

22}, Marie Müller^{6

22}, Henning Fenselau^{6

22

23}, Yin Liu²⁴, 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 Schmiel³⁰, Johannes Brägelmann^{1

3

15}, Tim Hucho^{19

20}, Silvia von Karstedt^{1

6

15}, Martin Peifer^{1

15}, Alessandro Annibaldi¹⁵, Robert Hänsel-Hertsch^{1

6

15

16}, Thorsten Persigehl³¹, Holger Grüll³¹, Martin L Sos^{1

32

33}, Guido Reifenberger³⁴, Matthias Fischer^{15

21}, Dirk Adriaensen¹¹, Reinhard Büttner³⁰, Julien Sage^{9

10}, Inge Brouns¹¹, Roland Rad¹³, Roman K Thomas^{1

30}, Max Anstötz³⁵, 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

Functional synapses between neurons and small cell lung cancer

Vignesh Sakthivelu et al. Nature. 2025.

. 2025 Sep 10.

doi: 10.1038/s41586-025-09434-9. Online ahead of print.

Authors

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

Erratum in

Publisher Correction: Functional synapses between neurons and small cell lung cancer.
Sakthivelu V, Schmitt A, Odenthal F, Ndoci K, Touet M, Shaib AH, Chihab A, Wani GA, Nieper P, Hartmann GG, Pintelon I, Kisis I, Boecker M, Eckert NM, Iannicelli Caiaffa M, Ibruli O, Weber J, Maresch R, Bebber CM, Chitsaz A, Lütz A, Kim Alves Carpinteiro M, Morris KM, Franchino CA, Benz J, Pérez-Revuelta L, Soriano-Campos JA, Huetzen MA, Goergens J, Jevtic M, Jahn-Kelleter HM, Zempel H, Placzek A, Hennrich AA, Conzelmann KK, Tumbrink HL, Hunold P, Isensee J, Werr L, Gaedke F, Schauss A, Minère M, Müller M, Fenselau H, Liu Y, Heimsoeth A, Gülcüler Balta GS, Walczak H, Frezza C, Jachimowicz RD, George J, Schmiel M, Brägelmann J, Hucho T, von Karstedt S, Peifer M, Annibaldi A, Hänsel-Hertsch R, Persigehl T, Grüll H, Sos ML, Reifenberger G, Fischer M, Adriaensen D, Büttner R, Sage J, Brouns I, Rad R, Thomas RK, Anstötz M, Rizzoli SO, Bergami M, Motori E, Reinhardt HC, Beleggia F. Sakthivelu V, et al. Nature. 2025 Sep 19. doi: 10.1038/s41586-025-09638-z. Online ahead of print. Nature. 2025. PMID: 40973832 No abstract available.

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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Conflict of interest statement

Competing interests: H.C.R. received consulting and lecture fees from Abbvie, AstraZeneca, Vertex and Merck. H.C.R. received research funding from AstraZeneca and Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics. R.K.T. is a founder of PearlRiver Bio (now part of Centessa), a shareholder of Centessa, a founder and shareholder of Epiphanes and a consultant to PearlRiver Bio and Epiphanes. R.K.T. has received research support from Roche. R.K.T. and J.S. are co-founders and shareholders of DISCO Pharmaceuticals. M.L.S. is a co-founder and was an advisor of PearlRiver Bio (now part of Centessa). M.L.S. received research funding from PearlRiver Bio (now part of Centessa). S.O.R. is a shareholder of NanoTag Biotechnologies. H.W. was a co-founder of Apogenix. J. George is a consultant to DISCO Pharmaceuticals and received honoraria from MSD and Boehringer Ingelheim. J. Brägelmann has received research funding from Bayer and travel grants from Merck and Bicycle Therapeutics. The other authors declare no competing interests.

References

1. Dingemans, A. M. C. et al. Small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 32, 839–853 (2021). - PubMed - DOI
1. Rudin, C. M., Brambilla, E., Faivre-Finn, C. & Sage, J. Small-cell lung cancer. Nat. Rev. Dis. Primers 7, 3 (2021).
1. Poirier, J. T. et al. New approaches to SCLC therapy: from the laboratory to the clinic. J. Thorac. Oncol. 15, 520–540 (2020). - PubMed - PMC - DOI
1. Zahalka, A. H. & Frenette, P. S. Nerves in cancer. Nat. Rev. Cancer 20, 143–157 (2020). - PubMed - PMC - DOI
1. Pan, C. & Winkler, F. Insights and opportunities at the crossroads of cancer and neuroscience. Nat. Cell Biol. 24, 1454–1460 (2022). - PubMed - DOI

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Functional synapses between neurons and small cell lung cancer

Affiliations

Functional synapses between neurons and small cell lung cancer

Authors

Affiliations

Erratum in

Abstract

Conflict of interest statement

References

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