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Sakthivelu, Vignesh ORCID: 0009-0000-1652-0850, Schmitt, Anna ORCID: 0009-0002-7655-1805, Odenthal, Franka ORCID: 0000-0003-4138-121X, Ndoci, Kristiano ORCID: 0000-0002-9896-8196, Touet, Marian ORCID: 0009-0004-7875-1880, Shaib, Ali H., Chihab, Abdulla ORCID: 0009-0002-1237-0087, Wani, Gulzar A. ORCID: 0000-0003-2380-5816, Nieper, Pascal ORCID: 0000-0003-0607-3561, Hartmann, Griffin G. ORCID: 0000-0001-9213-8995, Pintelon, Isabel, Kisis, Ilmars ORCID: 0000-0001-6207-3991, Boecker, Maike ORCID: 0009-0008-0595-8599, Eckert, Naja M. ORCID: 0009-0007-2888-0280, Iannicelli Caiaffa, Manoela ORCID: 0009-0007-0704-0397, Ibruli, Olta, Weber, Julia, Maresch, Roman ORCID: 0000-0003-3393-8882, Bebber, Christina M. ORCID: 0000-0002-7841-7493, Chitsaz, Ali, Lütz, Anna ORCID: 0009-0000-2891-7038, Kim Alves Carpinteiro, Mira ORCID: 0009-0009-9941-3027, Morris, Kaylee M. ORCID: 0009-0009-4455-2951, Franchino, Camilla A. ORCID: 0009-0002-4502-6514, Benz, Jonas ORCID: 0009-0007-6053-2796, Pérez-Revuelta, Laura ORCID: 0000-0002-9010-8220, Soriano-Campos, Jorge A. ORCID: 0000-0002-7237-8630, Huetzen, Maxim A. ORCID: 0009-0008-2217-813X, Goergens, Jonas, Jevtic, Milica, Jahn-Kelleter, Hannah M., Zempel, Hans ORCID: 0000-0002-7510-3077, Placzek, Aleksandra, Hennrich, Alexandru A. ORCID: 0000-0002-3233-6145, Conzelmann, Karl-Klaus ORCID: 0000-0002-8614-3656, Tumbrink, Hannah L. ORCID: 0009-0007-8256-7498, Hunold, Pascal ORCID: 0000-0002-7087-5908, Isensee, Joerg ORCID: 0000-0002-3390-0051, Werr, Lisa ORCID: 0000-0002-3697-4136, Gaedke, Felix ORCID: 0000-0002-7744-4940, Schauss, Astrid ORCID: 0000-0002-6658-2192, Minère, Marielle ORCID: 0000-0001-7889-9771, Müller, Marie, Fenselau, Henning ORCID: 0000-0001-7136-9751, Liu, Yin ORCID: 0000-0002-2377-2703, Heimsoeth, Alena ORCID: 0009-0008-9076-8537, Gülcüler Balta, Gülce S. ORCID: 0000-0002-3626-007X, Walczak, Henning ORCID: 0000-0002-6312-4591, Frezza, Christian ORCID: 0000-0002-3293-7397, Jachimowicz, Ron D. ORCID: 0000-0001-9522-7061, George, Julie ORCID: 0000-0002-4272-3683, Schmiel, Marcel, Brägelmann, Johannes ORCID: 0000-0002-1306-2169, Hucho, Tim ORCID: 0000-0002-4147-9308, von Karstedt, Silvia ORCID: 0000-0002-7816-5919, Peifer, Martin ORCID: 0000-0002-5243-5503, Annibaldi, Alessandro, Hänsel-Hertsch, Robert ORCID: 0000-0002-2835-4471, Persigehl, Thorsten ORCID: 0000-0001-5928-4405, Grüll, Holger ORCID: 0000-0002-0993-9300, Sos, Martin L. ORCID: 0000-0002-2868-100X, Reifenberger, Guido, Fischer, Matthias ORCID: 0000-0003-1363-1242, Adriaensen, Dirk, Büttner, Reinhard ORCID: 0000-0001-8806-4786, Sage, Julien ORCID: 0000-0002-8928-9968, Brouns, Inge, Rad, Roland ORCID: 0000-0002-6849-9659, Thomas, Roman K. ORCID: 0000-0001-9132-4876, Anstötz, Max ORCID: 0000-0003-3071-5835, Rizzoli, Silvio O. ORCID: 0000-0002-1667-7839, Bergami, Matteo ORCID: 0000-0001-5525-5025, Motori, Elisa ORCID: 0000-0001-5997-6866, Reinhardt, Hans Christian ORCID: 0000-0001-5706-9349 and Beleggia, Filippo ORCID: 0000-0003-0234-7094 (2025). Functional synapses between neurons and small cell lung cancer. Nature, 646 (8087). pp. 1243-1253. Nature Publ. Group. ISSN 0028-0836

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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 rate1–3. 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Sakthivelu, Vignesh UNSPECIFIED https://orcid.org/0009-0000-1652-0850 UNSPECIFIED Schmitt, Anna UNSPECIFIED https://orcid.org/0009-0002-7655-1805 UNSPECIFIED Odenthal, Franka UNSPECIFIED https://orcid.org/0000-0003-4138-121X UNSPECIFIED Ndoci, Kristiano UNSPECIFIED https://orcid.org/0000-0002-9896-8196 UNSPECIFIED Touet, Marian UNSPECIFIED https://orcid.org/0009-0004-7875-1880 UNSPECIFIED Shaib, Ali H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chihab, Abdulla UNSPECIFIED https://orcid.org/0009-0002-1237-0087 UNSPECIFIED Wani, Gulzar A. UNSPECIFIED https://orcid.org/0000-0003-2380-5816 UNSPECIFIED Nieper, Pascal UNSPECIFIED https://orcid.org/0000-0003-0607-3561 UNSPECIFIED Hartmann, Griffin G. UNSPECIFIED https://orcid.org/0000-0001-9213-8995 UNSPECIFIED Pintelon, Isabel UNSPECIFIED UNSPECIFIED UNSPECIFIED Kisis, Ilmars UNSPECIFIED https://orcid.org/0000-0001-6207-3991 UNSPECIFIED Boecker, Maike UNSPECIFIED https://orcid.org/0009-0008-0595-8599 UNSPECIFIED Eckert, Naja M. UNSPECIFIED https://orcid.org/0009-0007-2888-0280 UNSPECIFIED Iannicelli Caiaffa, Manoela UNSPECIFIED https://orcid.org/0009-0007-0704-0397 UNSPECIFIED Ibruli, Olta UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Maresch, Roman UNSPECIFIED https://orcid.org/0000-0003-3393-8882 UNSPECIFIED Bebber, Christina M. UNSPECIFIED https://orcid.org/0000-0002-7841-7493 UNSPECIFIED Chitsaz, Ali UNSPECIFIED UNSPECIFIED UNSPECIFIED Lütz, Anna UNSPECIFIED https://orcid.org/0009-0000-2891-7038 UNSPECIFIED Kim Alves Carpinteiro, Mira UNSPECIFIED https://orcid.org/0009-0009-9941-3027 UNSPECIFIED Morris, Kaylee M. UNSPECIFIED https://orcid.org/0009-0009-4455-2951 UNSPECIFIED Franchino, Camilla A. UNSPECIFIED https://orcid.org/0009-0002-4502-6514 UNSPECIFIED Benz, Jonas UNSPECIFIED https://orcid.org/0009-0007-6053-2796 UNSPECIFIED Pérez-Revuelta, Laura UNSPECIFIED https://orcid.org/0000-0002-9010-8220 UNSPECIFIED Soriano-Campos, Jorge A. UNSPECIFIED https://orcid.org/0000-0002-7237-8630 UNSPECIFIED Huetzen, Maxim A. UNSPECIFIED https://orcid.org/0009-0008-2217-813X UNSPECIFIED Goergens, Jonas UNSPECIFIED UNSPECIFIED UNSPECIFIED Jevtic, Milica UNSPECIFIED UNSPECIFIED UNSPECIFIED Jahn-Kelleter, Hannah M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zempel, Hans UNSPECIFIED https://orcid.org/0000-0002-7510-3077 UNSPECIFIED Placzek, Aleksandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Hennrich, Alexandru A. UNSPECIFIED https://orcid.org/0000-0002-3233-6145 UNSPECIFIED Conzelmann, Karl-Klaus UNSPECIFIED https://orcid.org/0000-0002-8614-3656 UNSPECIFIED Tumbrink, Hannah L. UNSPECIFIED https://orcid.org/0009-0007-8256-7498 UNSPECIFIED Hunold, Pascal UNSPECIFIED https://orcid.org/0000-0002-7087-5908 UNSPECIFIED Isensee, Joerg UNSPECIFIED https://orcid.org/0000-0002-3390-0051 UNSPECIFIED Werr, Lisa UNSPECIFIED https://orcid.org/0000-0002-3697-4136 UNSPECIFIED Gaedke, Felix UNSPECIFIED https://orcid.org/0000-0002-7744-4940 UNSPECIFIED Schauss, Astrid UNSPECIFIED https://orcid.org/0000-0002-6658-2192 UNSPECIFIED Minère, Marielle UNSPECIFIED https://orcid.org/0000-0001-7889-9771 UNSPECIFIED Müller, Marie UNSPECIFIED UNSPECIFIED UNSPECIFIED Fenselau, Henning UNSPECIFIED https://orcid.org/0000-0001-7136-9751 UNSPECIFIED Liu, Yin UNSPECIFIED https://orcid.org/0000-0002-2377-2703 UNSPECIFIED Heimsoeth, Alena UNSPECIFIED https://orcid.org/0009-0008-9076-8537 UNSPECIFIED Gülcüler Balta, Gülce S. UNSPECIFIED https://orcid.org/0000-0002-3626-007X UNSPECIFIED Walczak, Henning UNSPECIFIED https://orcid.org/0000-0002-6312-4591 UNSPECIFIED Frezza, Christian UNSPECIFIED https://orcid.org/0000-0002-3293-7397 UNSPECIFIED Jachimowicz, Ron D. UNSPECIFIED https://orcid.org/0000-0001-9522-7061 UNSPECIFIED George, Julie UNSPECIFIED https://orcid.org/0000-0002-4272-3683 UNSPECIFIED Schmiel, Marcel UNSPECIFIED UNSPECIFIED UNSPECIFIED Brägelmann, Johannes UNSPECIFIED https://orcid.org/0000-0002-1306-2169 UNSPECIFIED Hucho, Tim UNSPECIFIED https://orcid.org/0000-0002-4147-9308 UNSPECIFIED von Karstedt, Silvia UNSPECIFIED https://orcid.org/0000-0002-7816-5919 UNSPECIFIED Peifer, Martin UNSPECIFIED https://orcid.org/0000-0002-5243-5503 UNSPECIFIED Annibaldi, Alessandro UNSPECIFIED UNSPECIFIED UNSPECIFIED Hänsel-Hertsch, Robert UNSPECIFIED https://orcid.org/0000-0002-2835-4471 UNSPECIFIED Persigehl, Thorsten UNSPECIFIED https://orcid.org/0000-0001-5928-4405 UNSPECIFIED Grüll, Holger UNSPECIFIED https://orcid.org/0000-0002-0993-9300 UNSPECIFIED Sos, Martin L. UNSPECIFIED https://orcid.org/0000-0002-2868-100X UNSPECIFIED Reifenberger, Guido UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Matthias UNSPECIFIED https://orcid.org/0000-0003-1363-1242 UNSPECIFIED Adriaensen, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Büttner, Reinhard UNSPECIFIED https://orcid.org/0000-0001-8806-4786 UNSPECIFIED Sage, Julien UNSPECIFIED https://orcid.org/0000-0002-8928-9968 UNSPECIFIED Brouns, Inge UNSPECIFIED UNSPECIFIED UNSPECIFIED Rad, Roland UNSPECIFIED https://orcid.org/0000-0002-6849-9659 UNSPECIFIED Thomas, Roman K. UNSPECIFIED https://orcid.org/0000-0001-9132-4876 UNSPECIFIED Anstötz, Max UNSPECIFIED https://orcid.org/0000-0003-3071-5835 UNSPECIFIED Rizzoli, Silvio O. UNSPECIFIED https://orcid.org/0000-0002-1667-7839 UNSPECIFIED Bergami, Matteo UNSPECIFIED https://orcid.org/0000-0001-5525-5025 UNSPECIFIED Motori, Elisa UNSPECIFIED https://orcid.org/0000-0001-5997-6866 UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED https://orcid.org/0000-0001-5706-9349 UNSPECIFIED Beleggia, Filippo UNSPECIFIED https://orcid.org/0000-0003-0234-7094 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-811781
Identification Number:	10.1038/s41586-025-09434-9
Journal or Publication Title:	Nature
Volume:	646
Number:	8087
Page Range:	pp. 1243-1253
Number of Pages:	11
Date:	30 October 2025
Publisher:	Nature Publ. Group
ISSN:	0028-0836
Language:	English
Faculty:	External institution Faculty of Mathematics and Natural Sciences Faculty of Medicine
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Virologie > Institut für Virologie Faculty of Medicine > Weitere > Translationale Genomik Zentrum für Molekulare Medizin
Subjects:	Chemistry and allied sciences Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81178