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

Authors

Rebecca Lamb, The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester; The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of ManchesterFollow
Bela Ozsvari, The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester; The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of ManchesterFollow
Gloria Bonuccelli, The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester; The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of ManchesterFollow
Duncan L Smith, The Cancer Research UK Manchester Institute, University of ManchesterFollow
Richard Pestell, The Sidney Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Ubaldo E. Martinez-Outshoorn, MD, The Sidney Kimmel Cancer Center, Thomas Jefferson UniversityFollow
Robert B Clarke, The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of ManchesterFollow
Federica Sotgia, The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester; The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of ManchesterFollow
Michael P Lisanti, The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester; The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of ManchesterFollow

Document Type

Article

Publication Date

9-8-2015

Comments

This article has been peer reviewed. It was published in: Oncotarget.

Volume 6, Issue 26, 2015, Pages 21892-21905.

The published version is available at http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=5260&path[]=12355

Copyright © 2015 The Authors

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 is encoded by mt-DNA, this finding is indicative of increased mitochondrial biogenesis in hTERT-GFP(+) MCF7 cells. Importantly, most of these candidate biomarkers were transcriptionally over-expressed in human breast cancer epithelial cells in vivo. Similar results were obtained using cell size (forward/side scatter) to fractionate MCF7 cells. Larger stem-like cells also showed increased hTERT-GFP levels, as well as increased mitochondrial mass and function. Thus, this simple and rapid approach for the enrichment of immortal anabolic stem-like cancer cells will allow us and others to develop new prognostic biomarkers and novel anti-cancer therapies, by specifically and selectively targeting this metabolic sub-population of aggressive cancer cells. Based on our proteomics and functional analysis, FDA-approved inhibitors of protein synthesis and/or mitochondrial biogenesis, may represent novel treatment options for targeting these anabolic stem-like cancer cells.

Recommended Citation

Lamb, Rebecca; Ozsvari, Bela; Bonuccelli, Gloria; Smith, Duncan L; Pestell, Richard; Martinez-Outshoorn, MD, Ubaldo E.; Clarke, Robert B; Sotgia, Federica; and Lisanti, Michael P, "Dissecting tumor metabolic heterogeneity: Telomerase and large cell size metabolically define a sub-population of stem-like, mitochondrial-rich, cancer cells." (2015). Kimmel Cancer Center Faculty Papers. Paper 53.
https://jdc.jefferson.edu/kimmelccfp/53

PubMed ID

26323205