High mitochondrial mass identifies a sub-population of stem-like XXXX cells that are chemo-resistant.

@entity1 @entity0 @entity5 @entity19 @entity1311 @entity11707 @entity3 @entity4975
UNASSIGNED: Chemo-resistance is a clinical barrier to more effective anti- @entity5 therapy. In this context, @entity5 stem-like cells (CSCs) are thought to be chemo-resistant, resulting in @entity5 recurrence and distant @entity3 . Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic @entity0 @entity1 samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as @entity4975 dehydrogenase (ALDH) activity, and they were ESA+/ @entity11707 -/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12- m), relative to the smaller cell population (4-8- m). Moreover, the mito-high cell population showed a 2.4-fold enrichment in @entity5 -initiating cell activity, based on limiting dilution assays in @entity19 xenografts. Importantly, primary @entity1 breast CSCs isolated from @entity1 with metastatic @entity0 or a @entity1 derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to @entity1311 , resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of @entity0 cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population.
