Functional Dynamics of Neoplastic Cells and Central Synapses

Abstract

Metastatic brain tumors are a devastating class of brain cancers that produce debilitating neurological symptoms in humans eventually leading to death. However, the functional consequences of tumor cell integration with neuronal networks remains understudied. Here, we investigate the functional impact of tumor cells with a high propensity for brain metastasis. Using human neurons derived from stem cells, primary rat hippocampal neurons, and a mouse model of brain metastasis, we find that tumor cells dysregulate synaptic transmission between neurons via multiplicative synaptic scaling to alter neuronal excitability. Aberrant neuronal firing in the tumor microenvironment was sustained by synaptic NMDA receptor activation and reduced by the FDA approved NMDA receptor blocker memantine. Furthermore, monitoring synaptic transmission on tumor cells in hippocampal neuronal networks revealed a population of silent synapses on tumor cells that can be rapidly unlocked by overcoming metabotropic signaling from GABAB receptors. Unlocking these silent synapses accelerated cancer cell proliferation and revealed a regulated secretion from cancer cells during moments of neuronal hyperactivity. Together, these findings highlight how cancer cells dysregulate neuronal communication and establish a positive feedback loop that fuels cancer growth in hyperactive neuronal contexts. These results reveal potential therapeutic strategies to alleviate neurological symptoms and prevent cancer proliferation in patients with metastatic brain tumors.