Adeola O. Adebayo Michael,^1,2,16,17 Sungjin Ko,^1,2,16 Junyan Tao,^1,2 Akshata Moghe,^2,3 Hong Yang,^1,4 Meng Xu,^5,6 Jacquelyn O. Russell,^1,2 Tirthadipa Pradhan-Sundd,^1,2 Silvia Liu,^1,2 Sucha Singh,^1,2 Minakshi Poddar,^1,2 Jayvir S. Monga,¹ Pin Liu,⁷ Michael Oertel,^1,2 Sarangarajan Ranganathan,^2,8 Aatur Singhi,^2,9 Sandra Rebouissou,^10,11,12,13 Jessica Zucman-Rossi,^10,11,12,13 Silvia Ribback,¹⁴ Diego Calvisi,¹⁴ Natalia Qvartskhava,¹⁵ Boris Görg,¹⁵ Dieter Häussinger,¹⁵ Xin Chen,⁶ and Satdarshan P. Monga<sup>1,2,3,18,*

1</sup> Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
² Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
³ Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
⁴ Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
⁵ Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
⁶ Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, San Francisco, CA, USA
⁷ Department of Pediatrics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China
⁸ Division of Pediatric Pathology, Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
⁹ Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
¹⁰ Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Paris 75010, France
¹¹ Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, 75010 Paris, France
¹² Université Paris 13, Sorbonne Paris Cité, UFR SMBH, 93000 Bobigny, France
¹³ Université Paris Diderot, IUH, 75010 Paris, France
¹⁴ Institute of Pathology, University of Greifswald, Greifswald, Germany
¹⁵ Clinic for Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
¹⁶ These authors contributed equally
¹⁷ Present address: Georgia Institute of Technology, Atlanta, GA, USA
¹⁸ Lead Contact

^*Correspondence : Satdarshan P. Monga  

Based on their lobule location, hepatocytes display differential gene expression, including pericentral hepatocytes that surround the central vein, which are marked by Wnt-β-catenin signaling. Activating β-catenin mutations occur in a variety of liver tumors, including hepatocellular carcinoma (HCC), but no specific therapies are available to treat these tumor subsets. Here, we identify a positive relationship between β-catenin activation, its transcriptional target glutamine synthetase (GS), and p-mTOR-S2448, an indicator of mTORC1 activation. In normal livers of mice and humans, pericentral hepatocytes were simultaneously GS and p-mTOR-S2448 positive, as were β-catenin-mutated liver tumors. Genetic disruption of β-catenin signaling or GS prevented p-mTOR-S2448 expression, while its forced expression in β-catenin-deficient livers led to ectopic p-mTOR-S2448 expression. Further, we found notable therapeutic benefit of mTORC1 inhibition in mutant-β-catenin-driven HCC through suppression of cell proliferation and survival. Thus, mTORC1 inhibitors could be highly relevant in the treatment of liver tumors that are β-catenin mutated and GS positive.