The effects of restricted glycolysis on stem-cell like characteristics of breast cancer cells
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Arindam Banerjee1, Pardis Arvinrad1,2, Matthew Darley1, Stéphanie A. Laversin1,3, Rachel Parker1, Matthew J.J. Rose-Zerilli1,6, Paul A. Townsend5, Ramsey I. Cutress1,4,6, Stephen A. Beers1,3, Franchesca D. Houghton2,6, Charles N. Birts1,6 and Jeremy P. Blaydes1,6
1Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
2Centre for Human Development, Stem Cells & Regeneration, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
3Antibody & Vaccine Group, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
4University Hospital Southampton, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK
5Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Science Centre, University of Manchester, Manchester, M20 4QL, UK
6Institute for Life Sciences, University of Southampton, Southampton, SO17 1BJ, UK
Jeremy P. Blaydes, email: [email protected]
Keywords: breast cancer stem cell-like cells; metabolism; single-cell mRNA-seq; chemoresistance; glycolysis
Received: March 01, 2018 Accepted: April 08, 2018 Published: May 01, 2018
Altered glycolysis is a characteristic of many cancers, and can also be associated with changes in stem cell-like cancer (SCLC) cell populations. We therefore set out to directly examine the effect of glycolysis on SCLC cell phenotype, using a model where glycolysis is stably reduced by adapting the cells to a sugar source other than glucose. Restricting glycolysis using this approach consistently resulted in cells with increased oncogenic potential; including an increase in SCLC cells, proliferation in 3D matrigel, invasiveness, chemoresistance, and altered global gene expression. Tumorigenicity in vivo was also markedly increased. SCLC cells exhibited increased dependence upon alternate metabolic pathways. They also became c-KIT dependent, indicating that their apparent state of maturation is regulated by glycolysis. Single-cell mRNA sequencing identified altered networks of metabolic-, stem- and signaling- gene expression within SCLC-enriched populations in response to glycolytic restriction. Therefore, reduced glycolysis, which may occur in niches within tumors where glucose availability is limiting, can promote tumor aggressiveness by increasing SCLC cell populations, but can also introduce novel, potentially exploitable, vulnerabilities in SCLC cells.
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