“Functional Synapses between Small Cell Lung Cancer and Glutamatergic Neurons”, Anna Schmitt, Vignesh Sakthivelu, Kristiano Ndoci, Gulzar A. Wani, Marian Touet, Isabel Pintelon, Ilmars Kisis, Olta Ibruli, Julia Weber, Roman Maresch, Christina M. Bebber, Jonas Goergens, Milica Jevtic, Franka Odenthal, Aleksandra Placzek, Alexandru A. Hennrich, Karl-Klaus Conzelmann, Maike Boecker, Alena Heimsoeth, Gülce S. Gülcüler, Ron D. Jachimowicz, Julie George, Johannes Brägelmann, Silvia von Karstedt, Martin Peifer, Thorsten Persigehl, Holger Grüll, Martin L. Sos, Jens Brüning, Guido Reifenberger, Matthias Fischer, Dirk Adriaensen, Reinhard Büttner, Inge Brouns, Roland Rad, Roman K. Thomas, Matteo Bergami, Elisa Motori, Hans Christian Reinhardt, Filippo Beleggia2023-01-20 (neuroscience)⁠:

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer, characterized by rapid proliferation, early metastatic spread, clinical recurrence and high rate of mortality.

Using in vivo insertional mutagenesis screening in conjunction with cross-species genomic and transcriptomic validation, we identified a strong and consistent signal for neuronal, synaptic, and glutamatergic signaling gene sets in murine and human SCLC.

We show that SCLC cells have the ability to develop intimate contacts with neuronal glutamatergic terminals in vitro, in autochthonous primary lung tumors and in brain-engrafted tumors. These contacts can develop into bona fide synapses, allowing SCLC cells to receive glutamatergic inputs.

Fitting with a potential oncogenic role of neuron-SCLC interactions, we show that SCLC cells derive a robust proliferation advantage when co-cultured with neurons. Moreover, the repression of glutamate release and the stimulation of the inhibitory glutamate receptor GRM8 displayed therapeutic efficacy in an autochthonous mouse model of SCLC.

Therefore, following malignant transformation, SCLC cells appear to hijack glutamatergic signaling to sustain tumor growth, thereby exposing a novel entry route for therapeutic intervention.