Connectivity Map Analysis of a Single-Cell RNA-Sequencing -Derived Transcriptional Signature of mTOR Signaling

In the connectivity map (CMap) approach to drug repositioning and development, transcriptional signature of disease is constructed by differential gene expression analysis between diseased tissue or cells control. The negative correlation drug, a bioactive compound, assumed indicate its ability “reverse” process. A major limitation traditional CMaP use signatures derived from bulk tissues. Since key driver pathways are most likely dysregulated in only subset cells, “averaged” resulting lack resolution effectively identify effective therapeutic agents. single-cell RNA-seq (scRNA-seq) transcriptomic assay facilitates construction that specific individual cell types, but methods for using scRNA-seq data context lacking. Lymphangioleiomyomatosis (LAM) mutations TSC1 TSC2 genes result activation mTOR complex 1 (mTORC1). mTORC1 inhibitor Sirolimus FDA-approved treat LAM. Novel therapies LAM urgently needed as recurs with discontinuation treatment some patients insensitive drug. We developed constructing profiling applied them lung naïve sirolimus-treated patients. New successfully implicated inhibitors, including Sirolimus, capable reverting signatures. mimicking standard bulk-tissue failed detect any connection signaling. This indicates precise our crucial difference success failure treatments analysis.