The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells
Open accessAbstract
The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“High glycolytic flux is required to maintain upregulated PGD metabolism, and this in maintained in part through suppression of thioredoxin-interacting protein (TXNIP) transcription243.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [243]
Citations
Cites
Trapnell, C., Roberts, A., Goff, L. A., Pertea, G. M., Kim, D., Kelley, D. R., Pimentel, H., Salzberg, S. L., Rinn, J. L., & Pachter, L. S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.016 · Cited by 12,145
Siegel, R., Naishadham, D., & Jemal, A. (2012) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.20138 · Cited by 10,679
Spencer, P. M., Cameron, J. L., & Lin, L. (2000) · Cited by 7,202
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0155 · Cited by 7,094
Identification of Pancreatic Cancer Stem Cells
Li, C., Heidt, D. G., Dalerba, P. D., Burant, C., Zhang, L., Adsay, V. N., Wicha, M. S., Clarke, M. F., & Simeone, D. M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2030 · Cited by 3,419
Hermann, P. C., Huber, S. L., Herrler, T., Aicher, A., Ellwart, J. W., Guba, M. O., Bruns, C. J., & Heeschen, C. (2007) · Cell stem cell · doi:10.1016/j.stem.2007.06.002 · Cited by 2,946
Self-citationHidalgo, M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0901557 · Cited by 2,570
Association of reactive oxygen species levels and radioresistance in cancer stem cells
Diehn, M., Cho, R. W., Lobo, N. A., Kalisky, T., Dorie, M. J., Kulp, A. N., Qian, D., Lam, J. S., Ailles, L. E., Wong, M., et al. (2009) · Nature · doi:10.1038/nature07733 · Cited by 2,555
Lagadinou, E. D., Sach, A., Callahan, K. P., Rossi, R. M., Neering, S. J., Minhajuddin, M., Ashton, J. M., Pei, S., Grose, V., O’Dwyer, K. M., et al. (2013) · Cell stem cell · doi:10.1016/j.stem.2012.12.013 · Cited by 1,465
LeBleu, V. S., O’Connell, J. T., Herrera, K. N. G., Wikman, H., Pantel, K., Haigis, M. C., de Carvalho, F. M., Damascena, A. S., Chinen, L. T. D., Rocha, R. M., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3039 · Cited by 1,438
Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function
Viale, A., Pettazzoni, P., Lyssiotis, C. A., Ying, H., Sánchez, N., Marchesini, M., Carugo, A., Green, T., Seth, S., Giuliani, V., et al. (2014) · Nature · doi:10.1038/nature13611 · Cited by 1,259
Flicek, P., Amode, M. R., Barrell, D. G., Beal, K. M., Billis, K., Brent, S., Carvalho‐Silva, D., Clapham, P., Coates, G. M. P., Fitzgerald, S. F., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1196 · Cited by 1,242
Regulation of pgc-1α, a nodal regulator of mitochondrial biogenesis
Fernandez-Marcos, P. J., & Auwerx, J. (2011) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.110.001917 · Cited by 1,237
Wu, M., Neilson, A., Swift, A. L., Moran, R., Tamagnine, J., Parslow, D., Armistead, S., Lemire, K., Orrell, J., Teich, J., et al. (2006) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00247.2006 · Cited by 927
Loss of FBP1 by Snail-Mediated Repression Provides Metabolic Advantages in Basal-like Breast Cancer
Dong, C., Yuan, T., Wu, Y., Wang, Y., Fan, T. W. ‐., Miriyala, S., Lin, Y., Yao, J., Shi, J., Kang, T., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.01.022 · Cited by 821
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.003 · Cited by 818
Vazquez, F., Lim, J.-H., Chim, H., Bhalla, K., Girnun, G., Pierce, K., Clish, C. B., Granter, S. R., Widlund, H. R., Spiegelman, B. M., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2012.11.020 · Cited by 715
Energy Metabolism in Human Pluripotent Stem Cells and Their Differentiated Counterparts
Varum, S., Rodrigues, A. S., Moura, M. B., Momcilovic, O., Easley, C. A., Ramalho-Santos, J., Van Houten, B., & Schatten, G. (2011) · PLoS ONE · doi:10.1371/journal.pone.0020914 · Cited by 671
Stem cell metabolism in tissue development and aging
Shyh‐Chang, N., Daley, G. Q., & Cantley, L. C. (2013) · Development · doi:10.1242/dev.091777 · Cited by 602
Metabolic state of glioma stem cells and nontumorigenic cells
Vlashi, E., Lagadec, C. H., Vergnes, L., Matsutani, T., Masui, K., Poulou, M., Popescu, R., Donna, L. D., Evers, P. D., Dekmezian, C., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1106704108 · Cited by 565
Petronilli, V., Costantini, P., Scorrano, L., Colonna, R., Passamonti, S., & Bernardi, P. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)89437-1 · Cited by 533
Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells
Nakada, D., Saunders, T. L., & Morrison, S. J. (2010) · Nature · doi:10.1038/nature09571 · Cited by 524
Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cellsPreprint
Janiszewska, M., Suvà, M. L., Riggi, N., Houtkooper, R. H., Auwerx, J. H., Clément‐Schatlo, V., Radovanovic, I., Rheinbay, E., Provero, P., & Stamenkovic, I. (2012) · Genes & Development · doi:10.1101/gad.188292.112 · Cited by 454
Lonardo, E., Hermann, P. C., Mueller, M.-T., Huber, S. L., Balic, A., Miranda‐Lorenzo, I., Zagorac, S., Alcalá, S., Rodríguez-Arabaolaza, I., Ramírez, J. C., et al. (2011) · Cell stem cell · doi:10.1016/j.stem.2011.10.001 · Cited by 407
Self-citationThe Lkb1 metabolic sensor maintains haematopoietic stem cell survival
Gurumurthy, S., Xie, S. Z.-J., Alagesan, B., Kim, J., Yusuf, R. Z., Sáez, B., Tzatsos, A., Ozsolak, F., Milos, P. M., Ferrari, F., et al. (2010) · Nature · doi:10.1038/nature09572 · Cited by 407
Kordes, S., Pollak, M. N., Zwinderman, A. H., Mathôt, R. A., Weterman, M. J., Beeker, A., Punt, C. J., Richel, D. J., & Wilmink, J. W. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00027-3 · Cited by 361
Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer
Mueller, M., Hermann, P. C., Witthauer, J., Rubio‐Viqueira, B., Leicht, S. F., Huber, S. L., Ellwart, J. W., Mustafa, M., Bartenstein, P., D’Haese, J. G., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.05.053 · Cited by 348
Self-citationBatandier, C., Guigas, B., Detaille, D., El-Mir, M., Fontaine, E., Rigoulet, M., & Leverve, X. M. (2006) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-006-9003-8 · Cited by 279
Jimeno, A., Feldmann, G., Suárez‐Gauthier, A., Rasheed, Z. A., Solomon, A., Zou, G.-M., Rubio‐Viqueira, B., García-García, E., López‐Ríos, F., Matsui, W. H., et al. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0924 · Cited by 277
VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2
Zhao, D., Pan, C., Sun, J., Gilbert, C. A., Drews‐Elger, K., Azzam, D. J., Picon‐Ruiz, M., Kim, M., Ullmer, W., El‐Ashry, D., et al. (2014) · Oncogene · doi:10.1038/onc.2014.257 · Cited by 268
Mitochondrial and energy metabolism‐related properties as novel indicators of lung cancer stem cells
Ye, X., Li, Q., Wang, G., Sun, F., Gui-jun, H., Bian, X., Yu, S., & Qian, G. (2011) · International Journal of Cancer · doi:10.1002/ijc.25944 · Cited by 256
Nalls, D., Tang, S., Rodova, M., Srivastava, R. K., & Shankar, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0024099 · Cited by 255
Intracellular autofluorescence: a biomarker for epithelial cancer stem cells
Miranda‐Lorenzo, I., Dorado, J., Lonardo, E., Alcalá, S., Serrano, A. G., Clausell-Tormos, J., Cioffi, M., Megı́as, D., Zagorac, S., Balic, A., et al. (2014) · Nature Methods · doi:10.1038/nmeth.3112 · Cited by 209
Self-citationMetformin Targets the Metabolic Achilles Heel of Human Pancreatic Cancer Stem Cells
Lonardo, E., Cioffi, M., Sancho, P., Sanchez-Ripoll, Y., Trabulo, S. M. D., Dorado, J., Balic, A., Hidalgo, M. M., & Heeschen, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0076518 · Cited by 168
Self-citationAhuja, P., Zhao, P., Angelis, E., Ruan, H., Korge, P., Olson, A., Wang, Y., Jin, E. S., Jeffrey, F. M., Portman, M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci38331 · Cited by 157
Rizos, C. V., & Elisaf, M. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2013.02.038 · Cited by 155
ROS Links Glucose Metabolism to Breast Cancer Stem Cell and EMT Phenotype
Schieber, M., & Chandel, N. S. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.021 · Cited by 131
MicroRNAs as regulators and mediators of c-MYC function
Jackstadt, R., & Hermeking, H. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.04.003 · Cited by 117
Gallmeier, E., Hermann, P. C., Mueller, M.-T., Machado, J. G., Ziesch, A., Toni, E. N. D., Palagyi, A., Eisen, C., Ellwart, J. W., Rivera, J., et al. (2011) · Stem Cells · doi:10.1002/stem.595 · Cited by 106
Self-citationMYC Activates Stem-like Cell Potential in Hepatocarcinoma by a p53-Dependent Mechanism
Akita, H., Marquardt, J. U., Durkin, M. E., Kitade, M., Seo, D., Conner, E. A., Andersen, J. B., Factor, V. M., & Thorgeirsson, S. S. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0527 · Cited by 84
Oliveras‐Ferraros, C., Vázquez‐Martín, A., Cuyàs, E., Corominas-Faja, B., Rodríguez‐Gallego, E., Fernández‐Arroyo, S., Martı́n-Castillo, B., Joven, J., & Menéndez, J. A. (2014) · Cell Cycle · doi:10.4161/cc.27982 · Cited by 60
Lin, C.-H., Hung, P., & Chen, Y.-J. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140713266 · Cited by 24
Ferrari, A. C. R. D. C., Pfiffer, T., Alex, A. K., Nebuloni, D. R., Carneiro, A. Q., Capareli, F. C., Leite, L. A. S., Braghiroli, M. I., Lobo, J., Hoff, P. M., et al. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.e15196 · Cited by 12
Wilmink, J. W., Kordes, S., Zwinderman, A. H., Mathôt, R. A. A., Punt, C. J. A., & Richel, D. J. (2014) · Journal of Clinical Oncology · doi:10.1200/jco.2014.32.15_suppl.4021 · Cited by 10
Cited by
Sorted by citations
Batlle, E., & Clevers, H. (2017) · Nature Medicine · doi:10.1038/nm.4409 · Cited by 2,769
Vyas, S., Zaganjor, E., & Haigis, M. C. (2016) · Cell · doi:10.1016/j.cell.2016.07.002 · Cited by 1,735
Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321
Mitochondrial metabolism and cancer
Porporato, P. E., Filigheddu, N., Pedro, J. M. B., Kroemer, G., & Galluzzi, L. (2017) · Cell Research · doi:10.1038/cr.2017.155 · Cited by 1,323
Breast cancer: Biology, biomarkers, and treatments
Barzaman, K., Karami, J., Zarei‐Behjani, Z., Hosseinzadeh, A., Kazemi, M. H., Moradi‐Kalbolandi, S., Safari, E., & Farahmand, L. (2020) · International Immunopharmacology · doi:10.1016/j.intimp.2020.106535 · Cited by 1,072
Metadata
- Authors
- Sancho, P., Burgos-Ramos, E., Tavera, A., Bou Kheir, T., Jagust, P., Schoenhals, M., Barneda, D., Sellers, K., Campos-Olivas, R., Graña, O., Viera, C. R., Yuneva, M., Sainz, B., & Heeschen, C.
- Affiliations
- Queen Mary University of London (GB)
- Spanish National Cancer Research Centre (ES)
- Corresponding author
- Sancho, Patricia
- Heeschen, Christopher
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 22
- Issue
- 4
- Pages
- 590-605
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W1892036645
- Cited by
- 722
- References
- 44
- Citations by year
- 2026: 36 · 2025: 51 · 2024: 60 · 2023: 72 · 2022: 79 · 2021: 88 · 2020: 94 · 2019: 79 · 2018: 65 · 2017: 51 · 2016: 41 · 2015: 5
- FWCI
- 17.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- RUIdeRA - Institutional University Repository (University of Castilla-La Mancha) (submittedVersion, other-oa)
- Funders
- Francis Crick Institute (10223)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- pancreatic cancer stem cells, c-Myc, PGC-1α, metformin, oxidative phosphorylation, glycolysis, metabolic plasticity, drug resistance, mitochondrial reactive oxygen species, menadione, apoptosis, energy crisis, cancer metabolism
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, AC133 Antigen, Animals, Antineoplastic Agents, Glycoproteins, Humans, Metformin, Mice, Nude, Mitochondria, Oxidative Phosphorylation, Pancreatic Neoplasms, Peptides, Phenotype, Transcription Factors, Tumor Cells, Cultured, Neoplastic Stem Cells, Antigens, CD, Gene Library, Proto-Oncogene Proteins c-myc, Reactive Oxygen Species, Drug Resistance, Neoplasm, Vitamin K 3, RNA Interference, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
