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Cell Rep. 2015 Mar 10. pii: S2211-1247(15)00173-4. doi: 10.1016/j.celrep.2015.02.027. [Epub ahead of print]

YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.

Author information

1
Cancer Center , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Regenerative Medicine , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
2
Cancer Center , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA; Inserm U1053, University of Bordeaux, 146 rue Leo Saignat, 33076 Bordeaux Cedex, France.
3
Cancer Center , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Regenerative Medicine , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA.
4
Cancer Center , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
5
Cancer Center , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
6
Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
7
Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
8
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address: avruch@molbio.mgh.harvard.edu.
9
Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, Milan 20133, Italy.
10
Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; HCC Translational Research Laboratory, BCLC Group, Liver Unit, IDIBAPS, Hospital Clínic, CIBERehd, Universitat de Barcelona, 08036 Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain.
11
Cancer Center , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Center for Regenerative Medicine , Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA. Electronic address: bardeesy.nabeel@mgh.harvard.edu.

Abstract

Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.

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