Authors: Adeola O. Adebayo Michael, Sungjin Ko, Junyan Tao, Akshata Moghe, Hong Yang, Meng Xu, Jacquelyn O. Russell, Tirthadipa Pradhan-Sundd, Silvia Liu, Sucha Singh, Minakshi Poddar, Jayvir S. Monga, Pin Liu, Michael Oertel, Sarangarajan Ranganathan, Aatur Singhi, Sandra Rebouissou, Jessica Zucman-Rossi, Silvia Ribback, Diego Calvisi, Natalia Qvartskhava, Boris Görg, Dieter Häussinger, Xin Chen, Satdarshan P. Monga
Summary: 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.
Source: Cell Metabolism, 2019-01-31