YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression
Julien Fitamant,
Filippos Kottakis,
Samira Benhamouche,
Helen S. Tian,
Nicolas Chuvin,
Christine A. Parachoniak,
Julia M. Nagle,
Rushika M. Perera,
Marjorie Lapouge,
Vikram Deshpande,
Andrew X. Zhu,
Albert Lai,
Bosun Min,
Yujin Hoshida,
Joseph Avruch,
Daniela Sia,
Genís Campreciós,
Andrea I. McClatchey,
Josep M. Llovet,
David Morrissey,
Lakshmi Raj,
Nabeel Bardeesy
Affiliations
Julien Fitamant
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Filippos Kottakis
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Samira Benhamouche
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Helen S. Tian
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Nicolas Chuvin
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Christine A. Parachoniak
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Julia M. Nagle
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Rushika M. Perera
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Marjorie Lapouge
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Vikram Deshpande
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Andrew X. Zhu
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Albert Lai
Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA
Bosun Min
Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA
Yujin Hoshida
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
Joseph Avruch
Department of Molecular Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Daniela Sia
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
Genís Campreciós
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
Andrea I. McClatchey
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
Josep M. Llovet
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
David Morrissey
Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA
Lakshmi Raj
Novartis Institutes of Biomedical Research Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA
Nabeel Bardeesy
Cancer Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA
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.
