Pedro Molina-Sánchez1, Marina Ruiz de Galarreta1, Melissa A Yao2, Katherine E Lindblad2, Erin Bresnahan1, Elizabeth Bitterman1, Tiphaine C Martin3, Troy Rubenstein1, Kai Nie1, Jonathan Golas4, Shambhunath Choudhary5, Marina Bárcena-Varela1, Abdulkadir Elmas6, Veronica Miguela1, Ying Ding7, Zhengyan Kan7, Lauren Tal Grinspan1, Kuan-Lin Huang5, Ramon E Parsons3, David J Shields8, Robert A Rollins9, Amaia Lujambio10. 1. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 2. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York. 3. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Oncology R&D, Pfizer Inc, Pearl River, New York. 5. Drug Safety R&D, Pfizer Inc, Pearl River, New York. 6. Department of Genetics and Genomic Sciences, Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, New York. 7. Oncology R&D, Pfizer Inc, San Diego, California. 8. Oncology R&D, Pfizer Inc, Pearl River, New York. Electronic address: david.shields@pfizer.com. 9. Oncology R&D, Pfizer Inc, Pearl River, New York. Electronic address: robert.rollins@pfizer.com. 10. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: amaia.lujambio@mssm.edu.
Abstract
BACKGROUND AND AIMS: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. METHODS: By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. RESULTS: Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. CONCLUSIONS: This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
BACKGROUND AND AIMS: The pattern of genetic alterations in cancer driver genes in patients with hepatocellular carcinoma (HCC) is highly diverse, which partially explains the low efficacy of available therapies. In spite of this, the existing mouse models only recapitulate a small portion of HCC inter-tumor heterogeneity, limiting the understanding of the disease and the nomination of personalized therapies. Here, we aimed at establishing a novel collection of HCC mouse models that captured human HCC diversity. METHODS: By performing hydrodynamic tail-vein injections, we tested the impact of altering a well-established HCC oncogene (either MYC or β-catenin) in combination with an additional alteration in one of eleven other genes frequently mutated in HCC. Of the 23 unique pairs of genetic alterations that we interrogated, 9 were able to induce HCC. The established HCC mouse models were characterized at histopathological, immune, and transcriptomic level to identify the unique features of each model. Murine HCC cell lines were generated from each tumor model, characterized transcriptionally, and used to identify specific therapies that were validated in vivo. RESULTS: Cooperation between pairs of driver genes produced HCCs with diverse histopathology, immune microenvironments, transcriptomes, and drug responses. Interestingly, MYC expression levels strongly influenced β-catenin activity, indicating that inter-tumor heterogeneity emerges not only from specific combinations of genetic alterations but also from the acquisition of expression-dependent phenotypes. CONCLUSIONS: This novel collection of murine HCC models and corresponding cell lines establishes the role of driver genes in diverse contexts and enables mechanistic and translational studies.
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Authors: Jordi Barretina; Barry S Taylor; Shantanu Banerji; Alexis H Ramos; Mariana Lagos-Quintana; Penelope L Decarolis; Kinjal Shah; Nicholas D Socci; Barbara A Weir; Alan Ho; Derek Y Chiang; Boris Reva; Craig H Mermel; Gad Getz; Yevgenyi Antipin; Rameen Beroukhim; John E Major; Charles Hatton; Richard Nicoletti; Megan Hanna; Ted Sharpe; Tim J Fennell; Kristian Cibulskis; Robert C Onofrio; Tsuyoshi Saito; Neerav Shukla; Christopher Lau; Sven Nelander; Serena J Silver; Carrie Sougnez; Agnes Viale; Wendy Winckler; Robert G Maki; Levi A Garraway; Alex Lash; Heidi Greulich; David E Root; William R Sellers; Gary K Schwartz; Cristina R Antonescu; Eric S Lander; Harold E Varmus; Marc Ladanyi; Chris Sander; Matthew Meyerson; Samuel Singer Journal: Nat Genet Date: 2010-07-04 Impact factor: 38.330
Authors: Erin Bresnahan; Pedro Molina-Sánchez; Katherine E Lindblad; Barbara Maier; Marina Ruiz de Galarreta; Daniela Sia; Marc Puigvehi; Verónica Miguela; María Casanova-Acebes; Maxime Dhainaut; Carlos Villacorta-Martin; Aatur D Singhi; Akshata Moghe; Johann von Felden; Lauren Tal Grinspan; Shuang Wang; Alice O Kamphorst; Satdarshan P Monga; Brian D Brown; Augusto Villanueva; Josep M Llovet; Miriam Merad; Amaia Lujambio Journal: Cancer Discov Date: 2019-06-11 Impact factor: 39.397
Authors: Yujin Hoshida; Sebastian M B Nijman; Masahiro Kobayashi; Jennifer A Chan; Jean-Philippe Brunet; Derek Y Chiang; Augusto Villanueva; Philippa Newell; Kenji Ikeda; Masaji Hashimoto; Goro Watanabe; Stacey Gabriel; Scott L Friedman; Hiromitsu Kumada; Josep M Llovet; Todd R Golub Journal: Cancer Res Date: 2009-09-01 Impact factor: 12.701