Please use this identifier to cite or link to this item:
Title: YAP Inhibition restores Hepatocyte differentiation in advanced HCC, leading to tumor regression
Author: Fitamant, Julien
Kottakis, Filippos
Benhamouche, Samira
Tian, Helen S.
Chuvin, Nicolas
Parachoniak, Christine A.
Nagle, Julia M.
Perera, Rushika M.
Lapouge, Marjorie
Deshpande, Vikram
Zhu, Andrew X.
Lai, Albert
Min, Bosun
Hoshida, Yujin
Avruch, Joseph
Sia, Daniela
Campreciós Figueras, Genís
McClatchey, Andrea I.
Llovet i Bayer, Josep Maria
Morrissey, David
Raj, Lakshmi
Bardeesy, Nabeel
Keywords: Càncer de fetge
Proteïnes supressores de tumors
Cèl·lules hepàtiques
Diferenciació cel·lular
Liver cancer
Tumor suppressor protein
Liver cells
Cell diferentiation
Issue Date: 17-Mar-2015
Publisher: Elsevier
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.
Note: Reproducció del document publicat a:
It is part of: Cell Reports, 2015, vol. 10, num. 10
Related resource:
ISSN: 2211-1247
Appears in Collections:Articles publicats en revistes (Medicina)

Files in This Item:
File Description SizeFormat 
653945.pdf10.38 MBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons