Single cell multiomics unravel the transcription networks controlling the different EMT tumor states

Epithelial-to-mesenchymal transition (EMT) is a process by which cells lose their epithelial characteristics and acquire mesenchymal traits. In cancer, EMT is associated with tumor initiation, progression, invasion, metastasis and resistance to therapy. Recent studies demonstrated that EMT is not a binary switch, but presents intermediate states associated with different tumor functions. The gene regulatory networks (GRNs) controlling the different EMT states remain elusive. Here, using multi-OMIC approaches combining single cell RNA-seq and single cell ATAC-seq, we define the transcriptomic and chromatin landscape associated with the distinct EMT states in mouse skin squamous cell carcinoma (SCC) exhibiting EMT. Using CRISPR/Cas9-mediated loss of function studies combined with functional characterization in vitro and in vivo, we unravel the cellular and molecular mechanisms regulated by Pitx1, Klf5, Nfatc1 and Creb3l1, transcription factors (TFs) controlling specific EMT states. Altogether, our results identify the transcriptional and chromatin landscape of the distinct EMT tumor states and uncover novel key TFs controlling these states and their transition, providing potential novel targets for anti-cancer therapy.