Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression

Abstract

Neural activity is increasingly recognized as a critical 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, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. 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 largely unexplored. 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, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

Neuroscience and oncology: state-of-the-art and new perspectives

“…A current study finds that neuronal activity in remote contralateral brain regions stimulates the invasion of tumor cells enriched for axon guidance genes over the corpus callosum, with SEMA4F as the driving paracrine factor, promoting bidirectional brain-tumor signaling by remodeling tumor-adjacent neuronal synapses [21 && ]. Similar neuronal-activity dependent mechanism of tumor progression have now also been reported for SCLC, both for brain metastases and for the primary site in the lung [22].…”

Cancer hallmarks intersect with neuroscience in the tumor microenvironment

“…Thus, these two distinctive interfaces with the nervous system are implicated as substantive contributors to hallmark cancer phenotypes ( Figure 3 ). It is conceivable that tumor innervation and co-opted neuronal signaling in cancer cells will prove to modulate additional hallmark capabilities and associated parameters, e.g., phenotypic plasticity, 3 which has been recently demonstrated in small-cell lung cancer, 39 above and beyond those highlighted in Figure 3 ; such possibilities deserve future investigation. Finally, a metric for formal incorporation into the hallmarks of cancer schema has been a consensus for appreciable generality.…”

Direct excitatory synapses between neurons and tumor cells drive brain metastatic seeding of breast cancer and melanoma

“…Since it is known that OPCs also receive glutamatergic synaptic input via Ca 2+permeable AMPAR 8 , the finding of neurogliomal synapses [3][4][5] could have been interpreted as a lineagerestricted recapitulation, or hijacking, of neurodevelopmental features by the primary brain tumor cell. A similar principle could be assumed for extracranial cancers of neuroendocrine origin which also seemingly depend on glutamatergic synaptic signaling 6,28 . The existence of bona-fide neuron-cancer synapses on breast cancer and melanoma cells reported here points towards a much wider pathobiological role of neuron-tumor synapses.…”