RNA Therapeutics Institute; Medical Scientist Training Program; Graduate School of Biomedical Sciences; Program in Bioinformatics and Integrative Biology; Department of Surgery; Program in Molecular Medicine; Li Weibo Institute for Rare Diseases Research; Department of Molecular, Cell and Cancer Biology
Cancer Biology | Cell Biology | Digestive System Diseases | Hepatology | Neoplasms | Pediatrics
BACKGROUND and AIMS: Despite surgical and chemotherapeutic advances, the five-year survival rate for Stage IV Hepatoblastoma (HB), the predominant pediatric liver tumor, remains at 27%. YAP1 and beta-Catenin co-activation occurs in 80% of children's HB; however, a lack of conditional genetic models precludes tumor maintenance exploration. Thus, the need for a targeted therapy remains unmet. Given the predominance of YAP1 and beta-Catenin activation in HB, we sought to evaluate YAP1 as a therapeutic target in HB.
APPROACH and RESULTS: We engineered the first conditional HB murine model using hydrodynamic injection to deliver transposon plasmids encoding inducible YAP1(S127A) , constitutive beta-Catenin(DelN90) , and a luciferase reporter to murine liver. Tumor regression was evaluated using bioluminescent imaging, and tumor landscape characterized using RNA and ATAC sequencing, and DNA foot-printing. Here we show that YAP1(S127A) withdrawal mediates >90% tumor regression with survival for 230+ days in mice. YAP1 (S127A) withdrawal promotes apoptosis in a subset of tumor cells and in remaining cells 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. YAP1 (S127A) withdrawal drives formation of hbHeps by modulating liver differentiation transcription factor (TF) occupancy. Indeed, tumor-derived hbHeps, consistent with their reprogrammed transcriptional landscape, regain partial hepatocyte function and rescue liver damage in mice.
CONCLUSIONS: YAP1(S127A) withdrawal, without silencing oncogenic beta-Catenin, significantly regresses hepatoblastoma, providing the first in vivo data to support YAP1 as a therapeutic target for HB. YAP1(S127A) withdrawal alone sufficiently drives long-term regression in hepatoblastoma because it promotes cell death in a subset of tumor cells and modulates transcription factor occupancy to reverse the fate of residual tumor cells to mimic functional hepatocytes.
Liver cancer, Oncogene, Pediatric Cancer, Targeted Therapy, Therapeutic Differentiation
Rights and Permissions
Accepted manuscript posted with 12-month embargo as allowed by publisher's open access policy at https://authorservices.wiley.com/author-resources/Journal-Authors/open-access/author-compliance-tool.html.
DOI of Published Version
Smith JL, Rodríguez TC, Mou H, Kwan SY, Pratt H, Zhang XO, Cao Y, Liang S, Ozata DM, Yu T, Yin Q, Hazeltine M, Weng Z, Sontheimer EJ, Xue W. YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells. Hepatology. 2020 May 26. doi: 10.1002/hep.31389. Epub ahead of print. PMID: 32452550. Link to article on publisher's site
Hepatology (Baltimore, Md.)
Smith JL, T, Mou H, Kwan S, Pratt HE, Zhang X, Cao Y, Liang S, Ozata DM, Yu T, Yin Q, Hazeltine M, Weng Z, Sontheimer EJ, Xue W. (2020). YAP1 withdrawal in hepatoblastoma drives therapeutic differentiation of tumor cells to functional hepatocyte-like cells. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1002/hep.31389. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1698