Functional synapses between small cell lung cancer and glutamatergic neurons

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. ### Competing Interest Statement H.C.R. received consulting and lecture fees from Abbvie, AstraZeneca, Vertex and Merck. H.C.R. received research funding from Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics GmbH. R.K.T. is a founder of PearlRiver Bio (now part of Centessa), a shareholder of Centessa, founder and shareholder of Epiphanes Inc. and a consultant to PearlRiver Bio and Epiphanes Inc. RK Thomas has received research support from Roche. M.L.S. is a co-founder and was an advisor of PearlRiver Bio (a former Centessa company). M.L.S. received research funding from PearlRiver Bio (a former Centessa company). The remaining authors declare no competing financial interest.