Abstract
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.
Highlights
Major obstacles to treat cancer include chemoresistance, relapse and metastasis
We have demonstrated that restriction of glycolysis in cell lines derived from breast cancers of different subtypes, consistently results in an increase in the stem cell-like cancer (SCLC) cell population
This potential is consistent with Cuyas et al [39], who showed that enrichment of HMLER breast cancer cells for stem-like properties by inducing epithelialmesenchymal transition, resulted in their ability to metabolize a wider range of substrates, including fructose
Summary
Major obstacles to treat cancer include chemoresistance, relapse and metastasis. Stem cell-like cancer (SCLC) cells are critically involved in driving these processes [1]. Studies on breast cancer have demonstrated clear differences between SCLC cells and the bulk tumor cell population in their utilization of, and dependence on, specific metabolic pathways [3, 6, 7]. Some reports show that breast SCLC cells www.oncotarget.com are dependent on glycolysis [8], whereas others find higher mitochondrial oxidative phosphorylation in SCLC cells [3, 6] These contradictions are yet to be fully resolved, but represent some of the many examples of mechanistic interplay between major cellular metabolic pathways, the regulation of gene expression, and the control of stem cell maintenance [9,10,11]
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