Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

• DOI: 10.1016/j.cmet.2019.01.002
• Publication Date: 2019-02-01T03:42:24Z
• Authors: Adeola O. Adebayo...; Sungjin Ko; Junyan Tao; Akshata Moghe; Hong Yang; Meng Xu; Jacquelyn O. Russell; Tirthadipa Pradha...; Silvia Liu; Sucha Singh; Minakshi Poddar; Jayvir S. Monga; Pin Liu; Michael Oertel; Sarangarajan Rang...; Aatur Singhi; Sandra Rebouissou; Jessica Zucman-Rossi; Silvia Ribback; Diego Calvisi; Natalia Qvartskhava; Boris Görg; Dieter Häussinger; Xin Chen; Satdarshan P. Monga
• Keywords: Male; Glutamine; precision therapy; Medical Biochemistry and Metabolomics; Acetates; Inbred C57BL; Mice; Child; Wnt Signaling Pathway; beta Catenin; Cancer; Tumor; Liver Disease; TOR Serine-Threonine Kinases; Liver Neoplasms; glutamine synthetase; personalized medicine; 3. Good health; Child, Preschool; mTOR; Female; Liver Cancer; liver tumor; Carcinoma, Hepatocellular; Cell Survival; Knockout; Chronic Liver Disease and Cirrhosis; Mechanistic Target of Rapamycin Complex 1; Transfection; Cell Line; Wnt; Endocrinology & Metabolism; Rare Diseases; Phenols; Glutamate-Ammonia Ligase; Cell Line, Tumor; Genetics; Animals; Humans; metabolic zonation; Preschool; beta-catenin; glutamine synthetase; hepatocellular cancer; liver tumor; metabolic zonation; mTOR; personalized medicine; precision therapy; tumor metabolism; Wnt; Retrospective Studies; Cell Proliferation; Sirolimus; Animal; Carcinoma; Infant; Hepatocellular; beta-catenin; Mice, Inbred C57BL; Disease Models, Animal; hepatocellular cancer; Disease Models; Mutation; Hepatocytes; tumor metabolism; Biochemistry and Cell Biology; Digestive Diseases

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.