Integrating single-cell RNA-Seq with spatial transcriptomics in pancreatic ductal adenocarcinoma using multimodal intersection analysis

To understand tissue architecture, it is necessary to understand both which cell types are present and the physical relationships among them. Single-cell RNA-Seq (scRNA-Seq) has made significant progress towards the unbiased and systematic identification of cell populations within a tissue, however, the characterization of their spatial organization within it has been more elusive. The recently introduced ‘spatial transcriptomics’ method (ST) reveals the spatial pattern of gene expression within a tissue section at a resolution of a thousand 100 µm spots across the tissue, each capturing the transcriptomes of multiple cells. Here, we present an approach for the integration of scRNA-Seq and ST data generated from the same sample, and deploy it on primary pancreatic tumors from two patients. Applying our multimodal intersection analysis (MIA), we annotated the distinct micro-environment of each cell type identified by scRNA-Seq. We further found that subpopulations of ductal cells, macrophages, dendritic cells, and cancer cells have spatially restricted localizations across the tissue, as well as distinct co-enrichments with other cell types. Our mapping approach provides an efficient framework for the integration of the scRNA-Seq-defined subpopulation structure and the ST-defined tissue architecture in any tissue.