LGR5/mTORC2 axis regulates cellular metabolic plasticity to maintain tumorigenesis in hepatocellular carcinoma.

Cancer stem cells (CSCs)/tumor-initiating cells (TICs) withstand metabolic stress and maintain cell survival by means of metabolic reprogramming. However, the underlying mechanisms remain largely unclear. Additionally, it is unknown how to orchestrate metabolic vulnerability of CSCs. LGR5 has been implicated as a CSC marker in colorectal cancer, but in liver cancer, LGR5 has been less studied and its function is not yet explicit. Here, we showed that LGR5 can be used as a marker for liver cancer stem cells (LCSCs), and hepatocellular carcinoma (HCC) cells with high LGR5 expression are more metabolically plastic. In addition, we discovered that LGR5 promotes cancer cell survival by enhancing glycolytic capacity to resist glucose starvation. Mechanistically, LGR5 activates mTORC2 via the RAC1/AKT/FOXO3a axis to induce aerobic glycolysis during metabolic stress. Furthermore, given that p-AMPK was significantly reduced in HCC cells with high expression of LGR5, we found that metformin, an agonist of p-AMPK, inhibits the abnormal phenotypes of HCC cells both in vivo and in vitro by targeting metabolic vulnerabilities. Taken together, these findings establish LGR5 as an important regulator of glycolysis and suggest LGR5 as a potential therapeutic target for LCSCs.