- •The metabolic characteristics of cancer stem cells in cholangiocarcinoma are not known.
- •Cholangiocarcinoma stem-like cells preferentially use oxidative phosphorylation as a source of energy.
- •PGC-1α is a key molecule regulating the metabolic features of cholangiocarcinoma stem-like cells.
- •Interfering with oxidative phosphorylation or PGC-1α limits the development of tumors originating from stem-like cells in vivo.
- •Expression of PGC-1α or proteins of the mitochondrial respiratory complex correlate with clinical outcomes in patients with cholangiocarcinoma.
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.
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.
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.
The CCA stem-subset has a more efficient respiratory phenotype and depends on mitochondrial oxidative metabolism and PGC-1α to maintain CSC features.
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.
To read this article in full you will need to make a payment
Purchase one-time access:Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
One-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:Subscribe to Journal of Hepatology
Already a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
- Cholangiocarcinoma: epidemiology and risk factors.Liver Int. 2019; 39: 19-31
- Reply to: “Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinomaˮ.J Hepatol. 2019; 71: 1262-1263
- Cholangiocarcinoma 2020: the next horizon in mechanisms and management.Nat Rev Gastroenterol Hepatol. 2020; 17: 557-588
- Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA).Nat Rev Gastroenterol Hepatol. 2016; 13: 261-280
- The epidemiology of cholangiocarcinoma.Semin Liver Dis. 2004; 24: 115-125
- Discrete nature of EpCAM+ and CD90+ cancer stem cells in human hepatocellular carcinoma.Hepatology. 2013; 57: 1484-1497
- Cancer Stem cells and their cellular origins in primary liver and biliary tract cancers.Hepatology. 2016; 64: 645-651
- Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways.Hepatology. 2011; 54: 1031-1042
- Epigenetic reprogramming modulates malignant properties of human liver cancer.Hepatology. 2014; 59: 2251-2262
- Cancer stem cells and tumor-associated macrophages: a roadmap for multitargeting strategies.Oncogene. 2016; 35: 671-682
- Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts.J Hepatol. 2015; 62: 198-207
- Stem-like plasticity and heterogeneity of circulating tumor cells: current status and prospect challenges in liver cancer.Oncotarget. 2017; 8: 7094-7115
- Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages.J Hepatol. 2017; 66: 102-115
- Dysregulation of iron metabolism in cholangiocarcinoma stem-like cells.Sci Rep. 2017; 7: 17667
- Experimental models to unravel the molecular pathogenesis, cell of origin and stem cell properties of cholangiocarcinoma.Liver Int. 2019; 39: 79-97
- Cholest-4,6-Dien-3-One promote epithelial-to-mesenchymal transition (EMT) in biliary tree stem/progenitor cell cultures in vitro.Cells. 2019; 8
- Neoplastic transformation of the peribiliary stem cell niche in cholangiocarcinoma arisen in primary sclerosing cholangitis.Hepatology. 2019; 69: 622-638
- Role of glucose metabolism reprogramming in the pathogenesis of cholangiocarcinoma.Front Med (Lausanne). 2020; 7: 113
- PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect.Cell Death Dis. 2018; 9: 466
- Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells.Oncotarget. 2016; 7: 61890-61904
- Stromal-induced downregulation of miR-1247 promotes prostate cancer malignancy.J Cell Physiol. 2019; 234: 8274-8285
- Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1.Cell. 1999; 98: 115-124
- Hepatic peroxisome proliferator-activated receptor γ coactivator 1β drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice.Hepatology. 2018; 67: 884-898
- AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.Proc Natl Acad Sci U S A. 2007; 104: 12017-12022
- AMP-activated protein kinase is required for induction of apoptosis and epithelial-to-mesenchymal transition.Cell Signal. 2010; 22: 1790-1797
- TUFM downregulation induces epithelial-mesenchymal transition and invasion in lung cancer cells via a mechanism involving AMPK-GSK3β signaling.Cell Mol Life Sci. 2016; 73: 2105-2121
- PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure.Curr Opin Lipidol. 2009; 20: 98-105
- The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent.Mol Cancer Ther. 2014; 13: 596-605
- Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors.Gastroenterology. 2012; 142 (e1015): 1021-1031
- Selective chemical inhibition of PGC-1α gluconeogenic activity ameliorates type 2 diabetes.Cell. 2017; 169 (e115): 148-160
- Mitochondrial regulator PGC-1a-Modulating the modulator.Curr Opin Endocr Metab Res. 2019; 5: 37-44
- Metabolic differences in breast cancer stem cells and differentiated progeny.Breast Cancer Res Treat. 2014; 146: 525-534
- Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells.Genes Dev. 2012; 26: 1926-1944
- MYC/PGC-1α balance determines the metabolic phenotype and plasticity of pancreatic cancer stem cells.Cell Metab. 2015; 22: 590-605
- Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells.Oncotarget. 2015; 6: 14777-14795
- Cancer stem cells from epithelial ovarian cancer patients privilege oxidative phosphorylation, and resist glucose deprivation.Oncotarget. 2014; 5: 4305-4319
- Mitochondria as new therapeutic targets for eradicating cancer stem cells: quantitative proteomics and functional validation via MCT1/2 inhibition.Oncotarget. 2014; 5: 11029-11037
- PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis.Nat Cell Biol. 2014; 16 (1001-1015): 992-1003
- Therapeutic targets in cancer cell metabolism and autophagy.Nat Biotechnol. 2012; 30: 671-678
- SIRT1 facilitates hepatocellular carcinoma metastasis by promoting PGC-1α-mediated mitochondrial biogenesis.Oncotarget. 2016; 7: 29255-29274
- Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia.Proc Natl Acad Sci U S A. 2012; 109: 2784-2789
- Cutting edge: hypoxia-induced Nanog favors the intratumoral infiltration of regulatory T cells and macrophages via direct regulation of TGF-β1.J Immunol. 2013; 191: 5802-5806
- Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth.Proc Natl Acad Sci U S A. 1997; 94: 8104-8109
- Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor.Cancer Res. 2006; 66: 7843-7848
- Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptake.Nat Neurosci. 2013; 16: 1373-1382
- Metastatic breast cancer cells enter into dormant state and express cancer stem cells phenotype under chronic hypoxia.J Cell Biochem. 2017; 118: 3237-3248
- The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance.EMBO Mol Med. 2013; 5: 1196-1212
- Epithelial-mesenchymal transition programs and cancer stem cell phenotypes: mediators of breast cancer therapy resistance.Mol Cancer Res. 2020; 18: 1257-1270
- Guidelines and definitions for research on epithelial-mesenchymal transition.Nat Rev Mol Cell Biol. 2020; 21: 341-352
Published online: January 20, 2021
Accepted: December 24, 2020
Received in revised form: December 18, 2020
Received: March 22, 2020
Author names in bold designate shared co-first authorship
© 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.