Yuchen Liu1, Shu Zhuo1, Yaxing Zhou1, Lichun Ma2, Zhonghe Sun3, Xiaolin Wu3, Xin Wei Wang2, Bin Gao4, Yingzi Yang5. 1. Department of Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Ave. Boston, MA 02115, USA. 2. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. 3. Cancer Research Technology Program, Frederick National Laboratory for Cancer, Leidos Biomedical Research, Inc., Frederick, MD, 21702, USA. 4. 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. 5. 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.
Abstract
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.
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.
Authors: 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 Morrissey; Lakshmi Raj; Nabeel Bardeesy Journal: Cell Rep Date: 2015-03-12 Impact factor: 9.423
Authors: Alexander W Lange; Anusha Sridharan; Yan Xu; Barry R Stripp; Anne-Karina Perl; Jeffrey A Whitsett Journal: J Mol Cell Biol Date: 2014-12-05 Impact factor: 6.216
Authors: Hai Song; Kinglun Kingston Mak; Lilia Topol; Kangsun Yun; Jianxin Hu; Lisa Garrett; Yongbin Chen; Ogyi Park; Jia Chang; R Mark Simpson; Cun-Yu Wang; Bin Gao; Jin Jiang; Yingzi Yang Journal: Proc Natl Acad Sci U S A Date: 2010-01-08 Impact factor: 11.205
Authors: Li Lu; Ying Li; Soo Mi Kim; Wouter Bossuyt; Pu Liu; Qiong Qiu; Yingdi Wang; Georg Halder; Milton J Finegold; Ju-Seog Lee; Randy L Johnson Journal: Proc Natl Acad Sci U S A Date: 2010-01-04 Impact factor: 11.205
Authors: Yumeng Wang; Xiaoyan Xu; Dejan Maglic; Michael T Dill; Kamalika Mojumdar; Patrick Kwok-Shing Ng; Kang Jin Jeong; Yiu Huen Tsang; Daniela Moreno; Venkata Hemanjani Bhavana; Xinxin Peng; Zhongqi Ge; Hu Chen; Jun Li; Zhongyuan Chen; Huiwen Zhang; Leng Han; Di Du; Chad J Creighton; Gordon B Mills; Fernando Camargo; Han Liang Journal: Cell Rep Date: 2018-10-30 Impact factor: 9.423
Authors: Alireza Mowla; Rose Belford; Julia Köhn-Gaone; Nathan Main; Janina E E Tirnitz-Parker; George C Yeoh; Brendan F Kennedy Journal: Biomed Opt Express Date: 2022-09-01 Impact factor: 3.562
Authors: Antonio Cigliano; Shanshan Zhang; Silvia Ribback; Sara Steinmann; Marcella Sini; Cindy E Ament; Kirsten Utpatel; Xinhua Song; Jingxiao Wang; Maria G Pilo; Fabian Berger; Haichuan Wang; Junyan Tao; Xiaolei Li; Giovanni M Pes; Serena Mancarella; Gianluigi Giannelli; Frank Dombrowski; Matthias Evert; Diego F Calvisi; Xin Chen; Katja Evert Journal: J Exp Clin Cancer Res Date: 2022-06-03
Authors: Patricia de la Cruz-Ojeda; Tobias Schmid; Loreto Boix; Manuela Moreno; Víctor Sapena; Juan M Praena-Fernández; Francisco J Castell; Juan Manuel Falcón-Pérez; María Reig; Bernhard Brüne; Miguel A Gómez-Bravo; Álvaro Giráldez; Jordi Bruix; María T Ferrer; Jordi Muntané Journal: Cells Date: 2022-08-28 Impact factor: 7.666