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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2018.00677

“Energetic” Cancer Stem Cells (e-CSCs): A New Hyper-Metabolic and Proliferative Tumor Cell Phenotype, Driven by Mitochondrial Energy

  • 1School of Enviroment and Life Sciences, University of Salford, United Kingdom

Here, we provide the necessary evidence that mitochondrial metabolism drives the anchorage-independent proliferation of CSCs. Two human breast cancer cell lines, MCF7 (ER(+)) and MDA-MB-468 (triple-negative), were used as model systems. To directly address the issue of metabolic heterogeneity in cancer, we purified a new distinct sub-population of CSCs, based solely on their energetic profile. We propose the term “energetic” cancer stem cells (e-CSCs), to better describe this novel cellular phenotype. In a single step, we first isolated an auto-fluorescent cell sub-population, based on their high flavin-content, using flow-cytometry. Then, these cells were further subjected to a detailed phenotypic characterization. More specifically, e-CSCs were more glycolytic, with higher mitochondrial mass and showed significantly elevated oxidative metabolism. e-CSCs also demonstrated an increased capacity to undergo cell cycle progression, as well as enhanced anchorage-independent growth and ALDH-positivity. Most importantly, these e-CSCs could be effectively targeted by treatments with either i) OXPHOS inhibitors (DPI) or ii) a CDK4/6 inhibitor (Ribociclib). Finally, we were able to distinguish two distinct phenotypic sub-types of e-CSCs, depending on whether they were grown as 2D-monolayers or as 3D-spheroids. Remarkably, under 3D anchorage-independent growth conditions, e-CSCs were strictly dependent on oxidative mitochondrial metabolism. Unbiased proteomics analysis demonstrated the up-regulation of gene products specifically related to the anti-oxidant response, mitochondrial energy production and mitochondrial biogenesis. Therefore, mitochondrial inhibitors should be further developed as promising anti-cancer agents, to directly target and eliminate the “fittest” e-CSCs. Our results have important implications for using e-CSCs, especially those derived from 3D-spheroids, i) in tumor tissue bio-banking and ii) as a new cellular platform for drug development.

Keywords: Cancer stem-like cells (CSCs), Metabolism, mitochondrial OXPHOS, Glycolisis, Diphenyleneiodonium (DPI), Ribociclib

Received: 29 Oct 2018; Accepted: 21 Dec 2018.

Edited by:

Massimo Bonora, Department of Cell Biology, Albert Einstein College of Medicine, United States

Reviewed by:

Francesco De Francesco, Azienda Ospedaliero Universitaria Ospedali Riuniti, Italy
Cesar Cardenas, Centro de Biología Integrativa, Universidad Mayor, Chile  

Copyright: © 2018 Fiorillo, Sotgia and Lisanti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Federica Sotgia, School of Enviroment and Life Sciences, University of Salford, Salford, M5 4WT, Manchester, United Kingdom, fsotgia@gmail.com
Prof. Michael P. Lisanti, School of Enviroment and Life Sciences, University of Salford, Salford, M5 4WT, Manchester, United Kingdom, michaelp.lisanti@gmail.com