Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma
| Autor: | Matteo Ramazzotti, Luca Viganò, Mirella Pastore, Maria Letizia Taddei, Monika Lewinska, Javier Cibella, Clelia Peano, Erica Pranzini, Luca Di Tommaso, Elena Sacco, Jessica Iorio, Paola Chiarugi, S. Madiai, Jesper B. Andersen, Chiara Raggi, Ivan Orlandi, B. Piombanti, Giovanni Di Maira, Margherita Correnti, N. Navari, Tiziano Lottini, Annarosa Arcangeli, Giulia Lori, Claudia Campani, Fabio Marra |
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| Přispěvatelé: | Raggi, C, Taddei, M, Sacco, E, Navari, N, Correnti, M, Piombanti, B, Pastore, M, Campani, C, Pranzini, E, Iorio, J, Lori, G, Lottini, T, Peano, C, Cibella, J, Lewinska, M, Andersen, J, di Tommaso, L, Vigano, L, Di Maira, G, Madiai, S, Ramazzotti, M, Orlandi, I, Arcangeli, A, Chiarugi, P, Marra, F |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Indoles Carcinogenesis Propanols PGC-1α Mice SCID Mitochondrion Oxidative Phosphorylation Cholangiocarcinoma Mice Metformin/administration & dosage 0302 clinical medicine Mice Inbred NOD Signal Transduction/drug effects SR-18292 CCLP1 Propanols/administration & dosage Oxidative Phosphorylation/drug effects Electron Transport Complex II Indoles/administration & dosage OXPHOS Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/antagonists & inhibitors Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Phenotype Metformin Progression-Free Survival Mitochondria Tumor Burden Treatment Outcome Neoplastic Stem Cells 030211 gastroenterology & hepatology Epithelial-Mesenchymal Transition/drug effects Signal transduction Electron Transport Complex II/metabolism Tumor Burden/drug effects Signal Transduction Epithelial-Mesenchymal Transition Oxidative phosphorylation Biology Transfection 03 medical and health sciences HUCCT1 Neoplastic Stem Cells/metabolism Cancer stem cell Cell Line Tumor Mitochondria/metabolism Cholangiocarcinoma/drug therapy Animals Humans Gene silencing Gene Silencing Hepatology Bile Duct Neoplasms/drug therapy Carcinogenesis/drug effects Xenograft Model Antitumor Assays Embryonic stem cell 030104 developmental biology Bile Duct Neoplasms Mitochondrial biogenesis Cancer research |
| Zdroj: | Raggi, C, Taddei, M L, Sacco, E, Navari, N, Correnti, M, Piombanti, B, Pastore, M, Campani, C, Pranzini, E, Iorio, J, Lori, G, Lottini, T, Peano, C, Cibella, J, Lewinska, M, Andersen, J B, di Tommaso, L, Viganò, L, Di Maira, G, Madiai, S, Ramazzotti, M, Orlandi, I, Arcangeli, A, Chiarugi, P & Marra, F 2021, ' Mitochondrial oxidative metabolism contributes to a cancer stem cell phenotype in cholangiocarcinoma ', Journal of Hepatology, vol. 74, no. 6, pp. 1373-1385 . https://doi.org/10.1016/j.jhep.2020.12.031 |
| ISSN: | 0168-8278 |
| Popis: | BACKGROUND & AIMS: Little is known about the metabolic regulation of cancer stem cells (CSCs) in cholangiocarcinoma (CCA). We analyzed whether mitochondrial-dependent metabolism and related signaling pathways contribute to stemness in CCA.METHODS: The stem-like subset was enriched by sphere culture (SPH) in human intrahepatic CCA cells (HUCCT1 and CCLP1) and compared to cells cultured in monolayer. Extracellular flux analysis was examined by Seahorse technology and high-resolution respirometry. In patients with CCA, expression of factors related to mitochondrial metabolism was analyzed for possible correlation with clinical parameters.RESULTS: Metabolic analyses revealed a more efficient respiratory phenotype in CCA-SPH than in monolayers, due to mitochondrial oxidative phosphorylation. CCA-SPH showed high mitochondrial membrane potential and elevated mitochondrial mass, and over-expressed peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α, a master regulator of mitochondrial biogenesis. Targeting mitochondrial complex I in CCA-SPH using metformin, or PGC-1α silencing or pharmacologic inhibition (SR-18292), impaired spherogenicity and expression of markers related to the CSC phenotype, pluripotency, and epithelial-mesenchymal transition. In mice with tumor xenografts generated by injection of CCA-SPH, administration of metformin or SR-18292 significantly reduced tumor growth and determined a phenotype more similar to tumors originated from cells grown in monolayer. In patients with CCA, expression of PGC-1α correlated with expression of mitochondrial complex II and of stem-like genes. Patients with higher PGC-1α expression by immunostaining had lower overall and progression-free survival, increased angioinvasion and faster recurrence. In GSEA analysis, patients with CCA and high levels of mitochondrial complex II had shorter overall survival and time to recurrence.CONCLUSIONS: The CCA stem-subset has a more efficient respiratory phenotype and depends on mitochondrial oxidative metabolism and PGC-1α to maintain CSC features.LAY SUMMARY: The growth of many cancers is sustained by a specific type of cells with more embryonic characteristics, termed 'cancer stem cells'. These cells have been described in cholangiocarcinoma, a type of liver cancer with poor prognosis and limited therapeutic approaches. We demonstrate that cancer stem cells in cholangiocarcinoma have different metabolic features, and use mitochondria, an organelle located within the cells, as the major source of energy. We also identify PGC-1α, a molecule which regulates the biology of mitochondria, as a possible new target to be explored for developing new treatments for cholangiocarcinoma. |
| Databáze: | OpenAIRE |
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