TITLE : Comberons from single cell transcriptomics in endothelial cells

VEGF inhibitor drugs have been successful, especially in ophthalmology, but not all patients respond to them. Combinations of drugs are likely to be needed for a really effective therapy of angiogenesis-related diseases. In this paper we introduce a new concept, the comberon, a term named by analogy with the operon that refers to evolutionarily conserved combinations of co-expressed genes. These genes identify potential drug targets. Our results show that single-cell gene expression data can help to identify a set of co-expressed endothelial cell receptors, conserved among species (mice and human) and enriched, within a network, of connections to up-regulated genes. This set does include VEGF receptors and includes several other receptors previously shown to play a role in angiogenesis. The conclusions are supported by multiple highly significant statistical tests from large datasets, including an independent validation set. This discovery has broad pharmacological and socio-economic implications, going beyond angiogenesis therapy.