YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression
Open accessAbstract
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.
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Although a porto-central Yes-associated protein (YAP) expression gradient has been reported, the role of YAP/HIPPO signalling in metabolic zonation is unclear.
“Although a porto-central Yes-associated protein (YAP) expression gradient has been reported,55 the role of YAP/HIPPO signalling in metabolic zonation is unclear.”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [55]
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Cites
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Hippo Pathway Activity Influences Liver Cell Fate
Yimlamai, D., Christodoulou, C., Galli, G. G., Yanger, K., Pepe-Mooney, B., Gurung, B., Shrestha, K., Cahan, P., Stanger, B. Z., & Camargo, F. D. (2014) · Cell · doi:10.1016/j.cell.2014.03.060 · Cited by 857 · see citing works
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“Rather, we observed inhibition of E2F target genes and a pronounced reduction in cell proliferation followed by a gradual activation of a hepatocyte differentiation program, culminating in the morphologic differentiation of the HCCs into nodules resembling regenerative hepatocytes.”
InfluentialSelf-citationSchaub, J. R., Malato, Y., Gormond, C., & Willenbring, H. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.07.003 · Cited by 254 · cited 4× · see citing works
“…livers indicates that ADCs are derived from de-differentiation of hepatocytes (Yimlamai et al., 2014), consistent with emerging data demonstrating plasticity of these cells (Schaub et al., 2014; Yanger et al., 2014), and pointing to important functions of Hippo/YAP in controlling liver cell fate.”
InfluentialDifferential gene expression in periportal and perivenous mouse hepatocytes
Braeuning, A., Ittrich, C., Köhle, C., Hailfinger, S., Bonin, M., Buchmann, A., & Schwarz, M. (2006) · The FEBS Journal · doi:10.1111/j.1742-4658.2006.05503.x · Cited by 240 · see citing works
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“Notably, YAP has been shown to act as a switch for enhancer occupancy of HNF4A and FOXA2 in the liver, preventing expression of mature hepatocyte genes and promoting expression of liver stem cell (hepatoblast) genes (Alder et al., 2014).”
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- Authors
- 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., Morrissey, D., Raj, L., & Bardeesy, N.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Tisch Cancer Institute (US)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Avruch, Joseph
- Bardeesy, Nabeel
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 10
- Issue
- 10
- Pages
- 1692-1707
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4565791
- OpenAlex
- W2078811578
- Cited by
- 248
- References
- 9
- Citations by year
- 2026: 13 · 2025: 16 · 2024: 18 · 2023: 24 · 2022: 26 · 2021: 26 · 2020: 26 · 2019: 20 · 2018: 27 · 2017: 13 · 2016: 25 · 2015: 14
- FWCI
- 14.04
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (publishedVersion, cc-by)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- The Novartis Repository (Novartis) (submittedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute (P50CA127003, R01CA136567)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099558, T32DK007792)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Keywords
- YAP, Hippo signaling pathway, hepatocellular carcinoma, hepatocyte differentiation, hepatocyte reprogramming, tumor regression, HNF4α, CTNNB1, E2F transcription factors, hepatocyte quiescence
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