Activation of Tyrosine Metabolism in CD13(+) Cancer Stem Cells Drives Relapse in Hepatocellular Carcinoma

PURPOSE: Cancer stem cells (CSCs) are naturally resistant to chemotherapy, explaining why tumor relapse frequently occurs after initial regression upon administration of chemotherapeutic agents in most cases. A CSC population characterized by CD13 expression has been identified in hepatocellular carcinoma (HCC). In the current study, we aimed to clarify the molecular mechanism by which it escapes conventional therapies. MATERIALS AND METHODS: Here, we used flow cytometry to examine the percentage of CD13(+) CSCs in HepG2 and HuH7 cells after chemotherapy. Using in vitro isotope labeling technique, we compared metabolic pathways between CD13(+) and CD13(-) subpopulations. Using co-immunoprecipitation and western blotting, we determined the target expressions in protein levels under different conditions. We also performed immunohistochemistry to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of tyrosine metabolism in post-chemotherapeutic relapse in vivo. RESULTS: We observed that quiescent CD13(+) CSCs are enriched after chemotherapy in HCCs, and serve as a reservoir for recurrence. Mechanistically, CD13(+) CSCs were dependent on aerobic metabolism of tyrosine rather than glucose as energy source. Tyrosine metabolism also generated nuclear acetyl-CoA to acetylate and stabilize Foxd3, thereby allowing CD13(+) CSCs cells to sustain quiescence and resistance to chemotherapeutic agents. CONCLUSION: These findings encourage further exploration of eliminating CD13(+) cells by targeting specific metabolic pathways to prevent recurrence in HCCs.