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

Oncotarget
Rebecca LambMichael P Lisanti

Abstract

Tumor cell metabolic heterogeneity is thought to contribute to tumor recurrence, distant metastasis and chemo-resistance in cancer patients, driving poor clinical outcome. To better understand tumor metabolic heterogeneity, here we used the MCF7 breast cancer line as a model system to metabolically fractionate a cancer cell population. First, MCF7 cells were stably transfected with an hTERT-promoter construct driving GFP expression, as a surrogate marker of telomerase transcriptional activity. To enrich for immortal stem-like cancer cells, MCF7 cells expressing the highest levels of GFP (top 5%) were then isolated by FACS analysis. Notably, hTERT-GFP(+) MCF7 cells were significantly more efficient at forming mammospheres (i.e., stem cell activity) and showed increased mitochondrial mass and mitochondrial functional activity, all relative to hTERT-GFP(-) cells. Unbiased proteomics analysis of hTERT-GFP(+) MCF7 cells directly demonstrated the over-expression of 33 key mitochondrial proteins, 17 glycolytic enzymes, 34 ribosome-related proteins and 17 EMT markers, consistent with an anabolic cancer stem-like phenotype. Interestingly, MT-CO2 (cytochrome c oxidase subunit 2; Complex IV) expression was increased by >20-fold. As MT-CO2...Continue Reading

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Citations

Nov 5, 2019·Frontiers in Genetics·Sára Sándor, Enikő Kubinyi
Aug 4, 2020·World Journal of Stem Cells·Xuan ZhuZhi-Gang Chen
Nov 3, 2016·Nature Reviews. Clinical Oncology·Ubaldo E Martinez-OutschoornMichael P Lisanti
Jun 12, 2019·Cancer Microenvironment : Official Journal of the International Cancer Microenvironment Society·Mohd RihanAmit Khairnar
Oct 31, 2015·Oncotarget·Paola Chiarugi, Persio Dello Sbarba

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Methods Mentioned

BETA
FACS
protein folding
laser-capture microdissection
flow cytometry

Software Mentioned

Progenesis LCMS
FlowJo

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