Friday, 4 September 2015

Dissecting tumor metabolic heterogeneity: Telomerase and large cell size metabolically define a sub-population of stem-like, mitochondrial-rich, cancer cells

Rebecca Lamb, Bela Ozsvari, Gloria Bonuccelli, Duncan L. Smith, Richard G. Pestell, Ubaldo E. Martinez-Outschoorn, Robert B. Clarke, Federica Sotgia
and Michael P. Lisanti

Telomeres are regions of non-coding DNA, which protectively cap the ends of chromosomes. After successive rounds of replication, telomeres shorten because DNA polymerase does not duplicate DNA all the way to the end of a chromosome, and induces senescence after 50-70 divisions. Telomerase (hTERT) is an enzyme which lengthens nucleotides, the overexpression of which is sufficient to immortalize a cell.

Here, the authors fluorescently tag the promoter of hTERT with GFP, to select cancer cells with high telomerase transcriptional activity, and purify so-called cancer stem-like cells. The authors, studying breast cancer cells, found that cells in the top 5% of hTERT-expressing cells (GFP-high) formed ~2.5 times more mammospheres than the bottom 5% (GFP-low). GFP-high cells also showed a 1.7-fold increase in the median MitoTracker fluorescence, indicating a strongly increased mitochondrial content in these cells.

The authors also sorted their cells by size, taking the top ~15% as 'large' and the rest as 'small'. They found that larger cells possessed a ~2.7-fold increase in hTERT activity, and 1.6-fold increase in mitochondrial mass.


Is the correlation between cell size and mitochondrial content surprising? Do ordinary cells possess a larger mitochondrial content, because they have a larger cytoplasmic volume and therefore greater energy demand? The finding that large cells have greater hTERT activity is, I think, surprising on its own terms because DNA content is independent of cell size. But disambiguating variation of mitochondrial content with cell volume, from cancer stemness is an interesting statistical question I think.

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