Transcriptional signatures of cell-cell interactions are dependent on cellular context

Cell-cell interactions are often predicted from single-cell transcriptomics data based on observing receptor and corresponding ligand transcripts in cells. These predictions could theoretically be improved by inspecting the transcriptome of the receptor cell for evidence of gene expression changes in response to the ligand. It is commonly expected that a given receptor, in response to ligand activation, will have a characteristic downstream gene expression signature. However, this assumption has not been well tested. We used ligand perturbation data from both the high-throughput Connectivity Map resource and published transcriptomic assays of cell lines and purified cell populations to determine whether ligand signals have unique and generalizable transcriptional signatures across biological conditions. Most of the receptors we analyzed did not have such characteristic gene expression signatures – instead these signatures were highly dependent on cell type. Cell context is thus important when considering transcriptomic evidence of ligand signaling, which makes it challenging to build generalizable ligand-receptor interaction signatures to improve cell-cell interaction predictions. ### Competing Interest Statement The authors have declared no competing interest.