Key result
Retrodifferentiated hepatocellular carcinoma cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4, which is reversed by the PDK4 inhibitor dichloroacetate.
Why the study?
Human hepatocellular carcinoma heterogeneity promotes recurrence and therapeutic resistance, but the molecular effectors inducing metabolic reprogramming, chemoresistance, and invasiveness in retrodifferentiated cancer stem cells were not fully identified.
Restoring mitochondrial function with a PDK4 inhibitor in combination with chemotherapy overcomes cancer resistance in human hepatocellular carcinomas.
May inform HCC therapies targeting stem cell plasticity; leaves open clinical validation in prospective cohorts.
Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies. Gene expression profiling of HepaRG-SP and HepaRG-Spheres revealed enriched signatures related to cancer stem cells, metastasis, and recurrence and showed that HepaRG progenitors could retrodifferentiate into an immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells expressed high levels of cytokines triggering retrodifferentiation and displayed high migration and invasion potential. They also showed changes in mitochondrial activity with reduced membrane potential, low ATP production, and high lactate production. These changes were, in part, related to angiopoietin-like 4 (ANGPTL4)-induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Upregulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Therefore, restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCC. SIGNIFICANCE: Restoring mitochondrial function in human hepatocellular carcinomas overcomes cancer resistance.
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Fekir et al. (2019) studied Human hepatocellular carcinoma (HCC) (n=457). ANGPTL4 and PDK4 upregulation was evaluated on Metabolic reprogramming, chemoresistance, and invasiveness. Retrodifferentiated hepatocellular carcinoma cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4, which is reversed by the PDK4 inhibitor dichloroacetate.
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