title: High mitochondrial mass identifies a sub-population of stem-like cancer cells that are chemo-resistant.
abstract: Chemo-resistance is a clinical barrier to more effective anti-cancer therapy. In this context, cancer stem-like cells (CSCs) are thought to be chemo-resistant, resulting in tumor recurrence and distant metastasis. Our hypothesis is that chemo-resistance in CSCs is driven, in part, by enhanced mitochondrial function. Here, we used breast cell lines and metastatic breast cancer patient samples to begin to dissect the role of mitochondrial metabolism in conferring the CSC phenotype. More specifically, we employed fluorescent staining with MitoTracker (MT) to metabolically fractionate these cell lines into mito-high and mito-low sub-populations, by flow-cytometry. Interestingly, cells with high mitochondrial mass (mito-high) were specifically enriched in a number of known CSC markers, such as aldehyde dehydrogenase (ALDH) activity, and they were ESA+/CD24-/low and formed mammospheres with higher efficiency. Large cell size is another independent characteristic of the stem cell phenotype; here, we observed a >2-fold increase in mitochondrial mass in large cells (>12-μm), relative to the smaller cell population (4-8-μm). Moreover, the mito-high cell population showed a 2.4-fold enrichment in tumor-initiating cell activity, based on limiting dilution assays in murine xenografts. Importantly, primary human breast CSCs isolated from patients with metastatic breast cancer or a patient derived xenograft (PDX) also showed the co-enrichment of ALDH activity and mitochondrial mass. Most significantly, our investigations demonstrated that mito-high cells were resistant to paclitaxel, resulting in little or no DNA damage, as measured using the comet assay. In summary, increased mitochondrial mass in a sub-population of breast cancer cells confers a stem-like phenotype and chemo-resistance. As such, our current findings have important clinical implications for over-coming drug resistance, by therapeutically targeting the mito-high CSC population.
authors.affiliation: Cancer Stem Cell Research, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
authors.affiliation: The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Sotgia
authors.affiliation: The Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Manchester, UK.|The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D051927:CD24 Antigen / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D018874:Spheroids, Cellular; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D000972:Antineoplastic Agents, Phytogenic; D051927:CD24 Antigen; C497889:CD24 protein, human; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D000444:Aldehyde Dehydrogenase; D017239:Paclitaxel
keywords: MitoTracker; cancer stem cells; mitochondria; tumor metabolism