Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/103326
Title: YAP Inhibition restores Hepatocyte differentiation in advanced HCC, leading to tumor regression
Author: Fitamant, J.
Kottakis, F.
Benhamouche, S.
Tian, H.S.
Chuvin, N.
Parachoniak, C.A.
Nagle, J.M.
Perera, R.M.
Lapouge, M.
Deshpande, V.
Zhu, A.X.
Lai, A.
Min, B.
Hoshida, Y.
Avruch, J.
Sia, D.
Campreciós Figueras, Genís
McClatchey, A.I.
Llovet i Bayer, Josep Maria
Morrissey, D.
Raj, L.
Bardeesy, Nabeel
Keywords: Càncer de fetge
Tumors
Proteïnes supressores de tumors
Cèl·lules hepàtiques
Diferenciació cel·lular
Liver cancer
Tumors
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: https://doi.org/10.1016/j.celrep.2015.02.027
It is part of: Cell Reports, 2015, vol. 10, num. 10
Related resource: https://doi.org/10.1016/j.celrep.2015.02.027
URI: http://hdl.handle.net/2445/103326
ISSN: 2211-1247
Appears in Collections:Articles publicats en revistes (Medicina)

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