Jewell ML, Gibson JR, Guy CD, et al. - The single-cell RNA-sequencing was used in order to characterize a patient-derived Fibrolamellar carcinoma (FLC, which is identified by the in-frame fusion of DNAJB1 with PRKACA and by dense desmoplasia) xenograft model and recognize therapeutic targets. Human FLC cells segregated into four discrete clusters, each of them expressed the oncogene YAP1. The two communities most enriched with cells co-expressing FLC markers (CD68, AKAP12, KRT7, EPCAM, and CPS1) also had the most cells representing YAP1 and its pro-proliferative target genes (AREG, CCND1), which implies that these were proliferative FLC cell clusters. The other two clusters were enriched with cells expressing profibrotic YAP1 target genes, ACTA2, ELN, and COL1A1, designated that these were fibrogenic FLC cells. All clusters represented the YAP1 target gene and mesothelial progenitor marker MSLN, and many MSLN(+) cells co-expressed albumin. Trajectory analysis prognosticated that the four FLC communities were acquired from a single cell type transitioning between phenotypic states. Following building a novel FLC cell line that nurtured the DNAJB1-PRKACA fusion, YAP1 was restrained, which, in turn, notably decreased expression of known YAP1-target genes as well as cell growth and migration. Therefore, in a YAP1-dependent liver mesothelial progenitor, both FLC epithelial and stromal cells seem to originate from DNAJB1-PRKACA fusion, recognizing YAP1 as a target for FLC therapy.