Jewell ML, Gibson JR, Guy CD, et al. - Experts utilized single-cell RNA sequencing to identify a patient-derived fibrolamellar carcinoma (FLC, identified by in-frame fusion of DnaJ heat shock protein family member B1 [DNAJB1] with protein kinase cAMP-activated catalytic subunit α [PRKACA] and by dense desmoplasia) xenograft model and recognize therapeutic targets. As prognosticated by trajectory analysis, among phenotypic states, the four FLC communities were derived from a single cell type transitioning. Following building a novel FLC cell line that harbored the DNAJB1-PRKACA fusion, Yes-associated protein 1 (YAP1) was restrained, which notably decreased expression of known YAP1 target genes along with cell growth and migration. Therefore, in a YAP1-dependent liver mesothelial progenitor, both FLC epithelial and stromal cells seem to arise from DNAJB1-PRKACA fusion, recognizing YAP1 as a target for FLC therapy.