PMID- 34793870 OWN - NLM STAT- MEDLINE DCOM- 20220228 LR - 20230302 IS - 1600-0641 (Electronic) IS - 0168-8278 (Print) IS - 0168-8278 (Linking) VI - 76 IP - 3 DP - 2022 Mar TI - Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis. PG - 652-664 LID - S0168-8278(21)02182-6 [pii] LID - 10.1016/j.jhep.2021.11.010 [doi] AB - BACKGROUND & AIMS: Primary liver tumors comprise distinct subtypes. A subset of intrahepatic cholangiocarcinoma (iCCA) can arise from cell fate reprogramming of mature hepatocytes in mouse models. However, the underpinning of cell fate plasticity during hepatocarcinogenesis is still poorly understood, hampering therapeutic development for primary liver cancer. As YAP activation induces liver tumor formation and cell fate plasticity, we investigated the role of Sox9, a transcription factor downstream of Yap activation that is expressed in biliary epithelial cells (BECs), in Yap-induced cell fate plasticity during hepatocarcinogenesis. METHODS: To evaluate the function of Sox9 in YAP-induced hepatocarcinogenesis in vivo, we used several genetic mouse models of inducible hepatocyte-specific YAP activation with simultaneous Sox9 removal. Cell fate reprogramming was determined by lineage tracing and immunohistochemistry. The molecular mechanism underlying Yap and Sox9 function in hepatocyte plasticity was investigated by transcription and transcriptomic analyses of mouse and human liver tumors. RESULTS: Sox9, a marker of liver progenitor cells (LPCs) and BECs, is differentially required in YAP-induced stepwise hepatocyte programming. While Sox9 has a limited role in hepatocyte dedifferentiation to LPCs, it is required for BEC differentiation from LPCs. YAP activation in Sox9-deficient hepatocytes resulted in more aggressive HCC with enhanced Yap activity at the expense of iCCA-like tumors. Furthermore, we showed that 20% of primary human liver tumors were associated with a YAP activation signature, and tumor plasticity is highly correlated with YAP activation and SOX9 expression. CONCLUSION: Our data demonstrated that Yap-Sox9 signaling determines hepatocyte plasticity and tumor heterogeneity in hepatocarcinogenesis in both mouse and human liver tumors. We identified Sox9 as a critical transcription factor required for Yap-induced hepatocyte cell fate reprogramming during hepatocarcinogenesis. LAY SUMMARY: Sox9, a marker of liver progenitor cells and bile duct lining cells, is a downstream target of YAP protein activation. Herein, we found that YAP activation in hepatocytes leads to a transition from mature hepatocytes to liver progenitor cells and then to bile duct lining cells. Sox9 is required in the second step during mouse hepatocarcinogenesis. We also found that human YAP and SOX9 may play similar roles in liver cancers. CI - Copyright (c) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Liu, Yuchen AU - Liu Y AD - Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02115, USA. FAU - Zhuo, Shu AU - Zhuo S AD - Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02115, USA. FAU - Zhou, Yaxing AU - Zhou Y AD - Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02115, USA. FAU - Ma, Lichun AU - Ma L AD - Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. FAU - Sun, Zhonghe AU - Sun Z AD - Cancer Research Technology Program, Frederick National Laboratory for Cancer, Leidos Biomedical Research, Inc., Frederick, MD, 21702, USA. FAU - Wu, Xiaolin AU - Wu X AD - Cancer Research Technology Program, Frederick National Laboratory for Cancer, Leidos Biomedical Research, Inc., Frederick, MD, 21702, USA. FAU - Wang, Xin Wei AU - Wang XW AD - Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. FAU - Gao, Bin AU - Gao B AD - Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health, 5625 Fishers Lane, Room 2S-33, Bethesda, MD 20892, USA. FAU - Yang, Yingzi AU - Yang Y AD - Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02115, USA; Harvard Stem Cell Institute, Dana-Farber/Harvard Cancer Center, 188 Longwood Ave. Boston, MA 02115, USA; Program in Gastrointestinal Malignancies, Dana-Farber/Harvard Cancer Center, 188 Longwood Ave. Boston, MA 02115, USA. Electronic address: yingzi_yang@hsdm.harvard.edu. LA - eng GR - HHSN261200800001C/RC/CCR NIH HHS/United States GR - HHSN261200800001E/CA/NCI NIH HHS/United States GR - P30 CA006516/CA/NCI NIH HHS/United States GR - R01 CA222571/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural DEP - 20211115 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (SOX9 Transcription Factor) RN - 0 (SOX9 protein, human) RN - 0 (YAP-Signaling Proteins) SB - IM CIN - J Hepatol. 2022 Mar;76(3):503-505. PMID: 34929213 MH - Animals MH - Carcinoma, Hepatocellular/*genetics/physiopathology MH - Cell Differentiation/*genetics MH - Disease Models, Animal MH - Hepatocytes/metabolism/physiology MH - Liver Neoplasms/genetics/metabolism/*physiopathology MH - Mice MH - SOX9 Transcription Factor/genetics/metabolism MH - Signal Transduction/*genetics MH - YAP-Signaling Proteins/genetics/metabolism PMC - PMC8858854 MID - NIHMS1756836 OTO - NOTNLM OT - BEC OT - HCC OT - Hippo signaling OT - LPC OT - Sox9 OT - Yap OT - cell fate plasticity OT - iCCA OT - reprogramming COIS- Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. EDAT- 2021/11/19 06:00 MHDA- 2022/03/01 06:00 PMCR- 2023/03/01 CRDT- 2021/11/18 20:13 PHST- 2021/06/21 00:00 [received] PHST- 2021/10/14 00:00 [revised] PHST- 2021/11/04 00:00 [accepted] PHST- 2021/11/19 06:00 [pubmed] PHST- 2022/03/01 06:00 [medline] PHST- 2021/11/18 20:13 [entrez] PHST- 2023/03/01 00:00 [pmc-release] AID - S0168-8278(21)02182-6 [pii] AID - 10.1016/j.jhep.2021.11.010 [doi] PST - ppublish SO - J Hepatol. 2022 Mar;76(3):652-664. doi: 10.1016/j.jhep.2021.11.010. Epub 2021 Nov 15.