title: YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression.
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.
authors.affiliation: 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.
authors.forename: Julien
authors.initials: J
authors.lastname: Fitamant
authors.affiliation: 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.
authors.forename: Filippos
authors.initials: F
authors.lastname: Kottakis
authors.affiliation: 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.
authors.forename: Samira
authors.initials: S
authors.lastname: Benhamouche
authors.affiliation: 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.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Tian
authors.affiliation: 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.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chuvin
authors.affiliation: 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.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parachoniak
authors.affiliation: 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.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Nagle
authors.affiliation: 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.
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.affiliation: 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.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Lapouge
authors.affiliation: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.affiliation: Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.affiliation: Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Bosun
authors.initials: B
authors.lastname: Min
authors.affiliation: 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.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Avruch
authors.affiliation: 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.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sia
authors.affiliation: 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.
authors.forename: Genís
authors.initials: G
authors.lastname: Campreciós
authors.affiliation: Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA; Department of Pathology, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Andrea I
authors.initials: AI
authors.lastname: McClatchey
authors.affiliation: 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.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.affiliation: Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: David
authors.initials: D
authors.lastname: Morrissey
authors.affiliation: Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Raj
authors.affiliation: 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.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy