Functional synapses between neurons and small cell lung cancer
Abstract
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.
Article Details
Authors (75)
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