Small cell lung cancer induces synaptic scaling to alter neuronal excitability

Tumor cell plasticity in novel microenvironments is central to the integration and subsequent growth of metastatic cells. However, the functional consequences of tumor cell integration with central neurons remains understudied. Here, we address this question using small cell lung cancer (SCLC), which has an extraordinary propensity to metastasize to the brain in humans. Transcriptomic and electrophysiological analysis of SCLC cells in neuronal microenvironments reveal a predilection for GABAergic synapse formation between neurons and a subset of adjacent SCLC cells. This functional integration of SCLC with central neurons induces multiplicative synaptic upscaling and dysregulated neuronal excitability. Aberrant excitation in human neurons with SCLC is sustained by synaptic NMDA receptor activation and can be reduced by the FDA approved NMDA receptor blocker memantine. These findings reveal strategies to normalize tumor-induced exacerbation of aberrant neuronal activity. The following samples were generated and analyzed using scRNA-seq: 1) cerebral organoids alone, 2) NCI-H69 cells grown as 2D cell lines, and 3) NCI-H69 cells grown within cerebral organoids. Samples were processed through the particle-templated instant partition sequencing (PIP-seq) platform using Fluent Biosciences' PIPseqTM T2 3' Single Cell Capture and Lysis Kit v2.0. cDNA libraries were sequenced on an Illumina NovaSeq 6000 instrument at Vanderbilt University.