Pluto Bioinformatics

GSE146548: Inhibiting YAP1 in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells

Bulk RNA sequencing

Despite advances in surgical care and chemotherapeutic regimens, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and -Catenin co-activation occur in 80% of childrens HB; however, a lack of conditional genetic models precludes exploration of tumor maintenance and therapeutic targets. Thus, the clinical need for a targeted therapy remains unmet. Given the predominance of YAP1 and -catenin activation in childrens tumors, we sought to evaluate YAP1 as a therapeutic target in HB. We engineered the first conditional murine model of HB using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1S127A, constitutive -CateninDelN90, and a luciferase reporter to murine liver. Tumor regression was evaluated using in vivo bioluminescent imaging, and tumor landscape characterized using RNA sequencing, ATAC sequencing and DNA foot-printing. Here we show that YAP1 inhibition mediates >90% tumor regression with survival for 230+ days in mice. Mechanistically, YAP1 inhibition induces a cell fate switch driving therapeutic differentiation of HB tumors into Ki-67 negative hbHep cells with hepatocyte-like morphology and mature hepatocyte gene expression. SOURCE: Tomas,Christopher,Rodriguez (tomas.rodriguez@umassmed.edu) - Erik Sontheimer University of Massachusetts Medical School