The effects of restricted glycolysis on stem-cell like characteristics of breast cancer cells.
Arindam Banerjee, Pardis Arvinrad, Matthew Darley, Stéphanie A Laversin, Rachel Parker, Matthew J J Rose-Zerilli, Paul A Townsend, Ramsey I Cutress, Stephen A Beers, Franchesca D Houghton, Charles N Birts, Jeremy P Blaydes
Author Information
- Arindam Banerjee: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Pardis Arvinrad: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Matthew Darley: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Stéphanie A Laversin: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Rachel Parker: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Matthew J J Rose-Zerilli: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Paul A Townsend: Division of Molecular and Clinical Cancer Sciences, Manchester Cancer Research Centre, Manchester Academic Health Science Centre, University of Manchester, Manchester, M20 4QL, UK.
- Ramsey I Cutress: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Stephen A Beers: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Franchesca D Houghton: Centre for Human Development, Stem Cells & Regeneration, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Charles N Birts: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
- Jeremy P Blaydes: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
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 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.
