Cited by 727Cancer, Hypoxia, and MetabolismMetabolism, Diabetes, and CancerCancer Cells and Metastasis

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MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells

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Sancho, Patricia, Burgos-Ramos, Emma, Tavera, Alejandra, Bou Kheir, Tony, Jagust, Petra, Schoenhals, Matthieu, Barneda, David, Sellers, Katherine, Campos-Olivas, Ramon, Graña, Osvaldo, Viera, Catarina R., Yuneva, Mariia, Sainz, Bruno, Heeschen, Christopher·2015·Cell Metabolism

DOI 10.1016/j.cmet.2015.08.015

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Abstract

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.

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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
ORCID: Sancho, Patricia
Schoenhals, Matthieu
Barneda, David
Yuneva, Mariia
Heeschen, Christopher
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2015-10
Volume: 22
Issue: 4
Pages: 590-605
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2015.08.015
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
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

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MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells

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