Targeting Unique Metabolic Properties of Breast Tumor Initiating Cells

Abstract

Normal stem cells from a variety of tissues display unique metabolic properties compared to their more differentiated progeny. However, relatively little is known about heterogeneity of metabolic properties cancer stem cells, also called tumor initiating cells (TICs). In this study we show that, analogous to some normal stem cells, breast TICs have distinct metabolic properties compared to non-tumorigenic cancer cells (NTCs). Transcriptome profiling using RNA-Seq revealed TICs under-express genes involved in mitochondrial biology and mitochondrial oxidative phosphorylation and metabolic analyses revealed TICs preferentially perform glycolysis over oxidative phosphorylation compared to NTCs. Mechanistic analyses demonstrated that decreased expression and activity of pyruvate dehydrogenase (Pdh), a key regulator of oxidative phosphorylation, play a critical role in promoting the pro-glycolytic phenotype of TICs. Metabolic reprogramming via forced activation of Pdh preferentially eliminates TICs both in vitro and in vivo. Our findings reveal unique metabolic properties of TICs and demonstrate that metabolic reprogramming represents a promising strategy for targeting these cells.

Cancer metabolism in space and time: Beyond the Warburg effect

“…For ex am ple, a sub set of pu ta tive ovar ian can cer stem cells (CD44 My D88 ) has been found to dis play a gly colytic meta bolic pro file over OX PHOS for their ATP gen er a tion [205], and a sub set of breast can cer cells able to grow as spheres in creas ingly rely on aer o bic gly col y sis and PPP flux com pared to the same cells grown in ad her ent con di tions [206]. Also, mod u la tion of spe cific gly colytic en zymes (i.e., de creased ex pres sion and ac tiv ity of pyru vate de hy dro ge nase or in creased ex pres sion or ac tiv ity of lac tate de hy dro ge nase A [LDHA]) plays a crit i cal role in pro mot ing the pro gly colytic phe no type of CICs in breast tu mors [237] and CSCs in lung tu mors [238].…”

Signatures of breast cancer metastasis at a glance

“…In another study, by using fluorescence-activated cell sorting-based assays and gene-expression profiling at the singlecell level, Lawson et al demonstrated that metastatic cells retained a distinct gene expression signature that is composed of stem cell-, EMT-, pro-survival-and dormancy-associated genes (Lawson et al, 2015). Overall, many biologically relevant stem-like expression signatures have been reported (Borcherding et al, 2015;Feng et al, 2014), but, to our knowledge, no definite clinical validation or metaanalysis studies have been performed to provide robust molecular profiles of breast cancer stem cells. Thus, the extent to which breast cancer stem cell incidence and/or function holds important prognostic and therapeutic information remains to be elucidated (Ali et al, 2011;Rakha et al, 2009;Shipitsin et al, 2007).…”

Metabolism in embryonic and cancer stemness

“…These findings have significant implications for studies examining cancer metabolism and the Warburg effect. The vast majority of studies in this area have focused on the bulk populations of cancer cells, thus, obscuring the potential heterogeneity of cancer cell metabolism (Feng et al 2014). For this reason, relatively little is known about the metabolic properties of CSCs, also called tumor initiating cells (TICs) (Feng et al 2014).…”