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 MorrisseyLakshmi Raj, Nabeel Bardeesy

Research output: Contribution to journalArticle

91 Scopus citations

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 aparadigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach

Original languageEnglish (US)
Pages (from-to)1692-1707
Number of pages16
JournalCell Reports
Volume10
Issue number10
DOIs
StatePublished - Mar 17 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    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, G., McClatchey, A. I., Llovet, J. M., ... Bardeesy, N. (2015). YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression. Cell Reports, 10(10), 1692-1707. https://doi.org/10.1016/j.celrep.2015.02.027