“Energetic” cancer stem cells (e-CSCs) : a new hyper-metabolic and proliferative tumor cell phenotype, driven by mitochondrial energy

Fiorillo, M, Sotgia, F ORCID: https://orcid.org/0000-0003-2826-4529 and Lisanti, MP ORCID: https://orcid.org/0000-0003-2034-1382 2019, '“Energetic” cancer stem cells (e-CSCs) : a new hyper-metabolic and proliferative tumor cell phenotype, driven by mitochondrial energy' , Frontiers in Oncology, 8 (677) .

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Abstract

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 weremore 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.

Item Type:	Article
Schools:	Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title:	Frontiers in Oncology
Publisher:	Frontiers Media
ISSN:	2234-943X
Related URLs:	Publisher
Funders:	Lunella Biotech, Inc.
Depositing User:	USIR Admin
Date Deposited:	06 Feb 2019 12:14
Last Modified:	16 Feb 2022 00:43
URI:	https://usir.salford.ac.uk/id/eprint/49958

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