Single nucleus transcriptomics confirms cancer-cell-intrinsic synaptic signaling in small cell lung cancer

Small cell lung cancer (SCLC) is one of the deadliest lung malignancies, with fast-growing tumors that metastasize early and typically respond to initial treatment only briefly before recurring. Direct synaptic contacts between neurons and cancer cells had been documented in brain tumors such as gliomas, but no equivalent connections had been demonstrated for cancers originating outside the central nervous system. The authors performed an in vivo piggyBac transposon mutagenesis screen in the Rb1fl/fl;Trp53fl/fl (RP) autochthonous mouse model of SCLC, and a reanalysis of mutation and expression data from human SCLC patients. Across both species, the gene programs that emerged most strongly from these analyses pointed to neurons and synapses.

A central question was whether this synaptic signal was coming from the tumor cells themselves or from neurons and other supporting cells within the tumor microenvironment. To resolve this, the authors used the Evercode WT Mega workflow to generate single nucleus RNA sequencing (snRNA-seq) profiles from six tumors harvested from RP mice. Clustering separated the malignant compartment (identified by Calca, Chga, Syp, and Ncam1) from immune (Ptprc), stromal (Col1a2), epithelial (Sftpb), and endothelial (Cdh5) populations in the lung. Synaptic membrane and glutamatergic synapse gene sets were clearly concentrated within the cancer cell cluster. One gene stood out in particular, Grm8, an inhibitory metabotropic glutamate receptor, had been flagged across the study’s mouse and human genetic datasets as a candidate therapeutic target. In the snRNA-seq data, Grm8 expression was restricted to the tumor cells, matching the pattern seen in a re-analyzed human SCLC scRNA-seq dataset. These results complemented the study’s co-culture, electrophysiology, and optogenetic experiments. Together, they supported a broader conclusion that SCLC cells can co-opt neuronal synaptic machinery to fuel their own growth. That finding also points to a possible therapeutic angle, which the authors began exploring with two glutamatergic inhibitors, riluzole and DCPG.

Publication: Functional synapses between neurons and small cell lung cancer: https://www.nature.com/articles/s41586-025-09434-9