Extracting Intercellular Signaling Network of Cancer Tissues Using Ligand-Receptor Expression Patterns from Whole-tumor and Single-cell Transcriptomes

Many behaviors of cancer, such as progression, metastasis and drug resistance etc., cannot be fully understood by genetic mutations or intracellular signaling alone. Instead, they are emergent properties of the cell community which forms a tumor. Studies of tumor heterogeneity reveal that many cancer behaviors critically depend on intercellular communication between cancer cells themselves and between cancer-stromal cells by secreted signaling molecules (ligands) and their cognate receptors. We analyzed public cancer transcriptome database for changes in cell-cell interactions as the characteristic of malignancy. We curated a list (>2,500 ligand-receptor pairs) and identified their joint enrichment in tumors from TCGA pan-cancer data. From single-cell RNA-Seq data for a case of melanoma and the specificity of the ligand-receptor interactions and their gene expression measured in individual cells, we constructed a map of a cell-cell communication network that indicates what signal is exchanged between which cell types in the tumor. Such networks establish a new formal phenotype of cancer which captures the cell-cell communication structure - it may open new opportunities for identifying molecular signatures of coordinated behaviors of cancer cells as a population - in turn may become a determinant of cancer progression potential and prognosis.