Retrodifferentiation of human tumor hepatocytes to stem cells leads to metabolic reprogramming and chemoresistance

Autor: Orlando Musso, Anne Corlu, Bernard Fromenty, Karim Fekir, Florian Cabillic, Hélène Dubois-Pot-Schneider, Fabrice Morel, Romain Desert, Yoann Daniel, Claudine Rauch, Denise Glaise
Přispěvatelé: Nutrition, Métabolismes et Cancer (NuMeCan), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut National de la Santé et de la Recherche Médicale (INSERM), Cancéropôle Grand Ouest, Association pour la Recherche sur le CancerAssociation pour la Recherche sur le Cancer (ARC), University of Rennes, Ligue Contre le CancerLigue Contre le Cancer, Conseil Régional de BretagneConseil Régional de Bretagne (Brittany Council), Institut National de la Santé et de la Recherche MédicaleInstitut National de la Santé et de la Recherche Médicale (Inserm), 223317, Seventh Framework ProgrammeSeventh Framework Programme (FP7), 12688, Institut National Du CancerInstitut National Du Cancer (INCa), Centre National de la Recherche ScientifiqueCentre National de la Recherche Scientifique (CNRS), Contrat plan etat region, Institut National de la Recherche Agronomique (INRA)-Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Cancer Research
Cancer Research, American Association for Cancer Research, 2019, 79 (8), pp.1869-1883. ⟨10.1158/0008-5472.CAN-18-2110⟩
Cancer Research, 2019, 79 (8), pp.1869-1883. ⟨10.1158/0008-5472.CAN-18-2110⟩
ISSN: 0008-5472
1538-7445
DOI: 10.1158/0008-5472.CAN-18-2110⟩
Popis: 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.
Databáze: OpenAIRE
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