CellNeighborEX : deciphering neighbor‐dependent gene expression from spatial transcriptomics data

Abstract

Cells have evolved their communication methods to sense their microenvironments and send biological signals. In addition to communication using ligands and receptors, cells use diverse channels including gap junctions to communicate with their immediate neighbors. Current approaches, however, cannot effectively capture the influence of various microenvironments. Here, we propose a novel approach to investigate cell neighbor ‐dependent gene ex pression (CellNeighborEX) in spatial transcriptomics (ST) data. To categorize cells based on their microenvironment, CellNeighborEX uses direct cell location or the mixture of transcriptome from multiple cells depending on ST technologies. For each cell type, CellNeighborEX identifies diverse gene sets associated with partnering cell types, providing further insight. We found that cells express different genes depending on their neighboring cell types in various tissues including mouse embryos, brain, and liver cancer. Those genes are associated with critical biological processes such as development or metastases. We further validated that gene expression is induced by neighboring partners via spatial visualization. The neighbor‐dependent gene expression suggests new potential genes involved in cell–cell interactions beyond what ligand‐receptor co‐expression can discover. image CellNeighborEX is a computational tool for exploring transcriptomic changes caused by direct cell contact in spatial transcriptomics data. CellNeighborEX provides a new perspective on cellular communication between two adjacent cells. CellNeighborEX identifies neighbor‐dependent genes in spatial transcriptomics data. CellNeighborEX presents new genes potentially involved in cell‐cell interactions, going beyond previous approaches that use ligand‐receptor pairs. Analyses with CellNeighborEX show that niche‐specific gene expression accounts for cellular heterogeneity.