Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Pathogenesis
Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is less well understood. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic cortical neuronal activity each drive proliferation of SCLC in the brain through both paracrine and synaptic neuron-cancer interactions. In the brain, SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity. SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation and development, highlighting a critical role for innervation in overall SCLC growth. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both the lung and the brain. Overall design: Single cell transcriptomic profiling of the SCLC cells using co-culture systems in which cortically derived murine neurons, representing a mixture of glutamatergic and GABA-ergic subpopulations, were cultured together with murine 16T line of SCLC cells. In both cases, the presence of active neurons significantly increased the rate of proliferation of SCLC cells in co-culture. This effect was abrogated with the addition of tetrodotoxin (TTX), a voltage-gated sodium channel blocker that silences neuronal action potentials.