CD10−/ALDH− cells are the sole cisplatin-resistant component of a novel ovarian cancer stem cell hierarchy

• Published in: Cell death & disease Vol. 8; no. 10; p. e3128
• Main Authors: Ffrench, Brendan, Gasch, Claudia, Hokamp, Karsten, Spillane, Cathy, Blackshields, Gordon, Mahgoub, Thamir Mahmoud, Bates, Mark, Kehoe, Louise, Mooney, Aoibhinn, Doyle, Ronan, Doyle, Brendan, O'Donnell, Dearbhaile, Gleeson, Noreen, Hennessy, Bryan T, Stordal, Britta, O'Riain, Ciaran, Lambkin, Helen, O'Toole, Sharon, O'Leary, John J, Gallagher, Michael F
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/100; 13/31; 13/51; 38/39; 38/61; 64/60; 692/699/67/1059/2326; 692/699/67/1059/99; 692/699/67/1517/1709; 692/699/67/71; Aldehyde dehydrogenase; Antibodies; Biochemistry; Cell Biology; Cell Culture; Chemoresistance; Chemotherapy; Cisplatin; DNA damage; DNA repair; Immunology; Life Sciences; Original; original-article; Ovarian cancer; Paclitaxel; Stem cells; Tumors
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2017.379

It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. However, little is known of the mechanisms involved, particularly with respect to the organisation of CSCs as stem-progenitor-differentiated cell hierarchies. Here we aimed to elucidate the relationship between CSC hierarchies and chemoresistance in an ovarian cancer model. Using a single cell-based approach to CSC discovery and validation, we report a novel, four-component CSC hierarchy based around the markers cluster of differentiation 10 (CD10) and aldehyde dehydrogenase (ALDH). In a change to our understanding of CSC biology, resistance to chemotherapy drug cisplatin was found to be the sole property of CD10
−
/ALDH
−
CSCs, while all four CSC types were sensitive to chemotherapy drug paclitaxel. Cisplatin treatment quickly altered the hierarchy, resulting in a three-component hierarchy dominated by the cisplatin-resistant CD10
−
/ALDH
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CSC. This organisation was found to be hard-wired in a long-term cisplatin-adapted model, where again CD10
−
/ALDH
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CSCs were the sole cisplatin-resistant component, and all CSC types remained paclitaxel-sensitive. Molecular analysis indicated that cisplatin resistance is associated with inherent- and adaptive-specific drug efflux and DNA-damage repair mechanisms. Clinically, low CD10 expression was consistent with a specific set of ovarian cancer patient samples. Collectively, these data advance our understanding of the relationship between CSC hierarchies and chemoresistance, which was shown to be CSC- and drug-type specific, and facilitated by specific and synergistic inherent and adaptive mechanisms. Furthermore, our data indicate that primary stage targeting of CD10
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/ALDH
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CSCs in specific ovarian cancer patients in future may facilitate targeting of recurrent disease, before it ever develops.