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Prostate cancer-derived holoclones: a novel and effective model for evaluating cancer stemness

2020; Nature Portfolio; Volume: 10; Issue: 1 Linguagem: Inglês

10.1038/s41598-020-68187-9

2045-2322

Louise Flynn, Martin P. Barr, Anne‐Marie Baird, Paul Smyth, Órla Casey, Gordon Blackshields, John Greene, Stephen R. Pennington, Emily Hams, Padraic G. Fallon, John O’Leary, Orla Sheils, Stephen P. Finn,

Cancer Genomics and Diagnostics

Abstract Prostate cancer accounts for approximately 13.5% of all newly diagnosed male cancer cases. Significant clinical burdens remain in terms of ineffective prognostication, with overtreatment of insignificant disease. Additionally, the pathobiology underlying disease heterogeneity remains poorly understood. As the role of cancer stem cells in the perpetuation of aggressive carcinoma is being substantiated by experimental evidence, it is crucially important to understand the molecular mechanisms, which regulate key features of cancer stem cells. We investigated two methods for in vitro cultivation of putative prostate cancer stem cells based on ‘high-salt agar’ and ‘monoclonal cultivation’. Data demonstrated ‘monoclonal cultivation’ as the superior method. We demonstrated that ‘holoclones’ expressed canonical stem markers, retained the exclusive ability to generate poorly differentiated tumours in NOD/SCID mice and possessed a unique mRNA-miRNA gene signature. miRNA:Target interactions analysis visualised potentially critical regulatory networks, which are dysregulated in prostate cancer holoclones. The characterisation of this tumorigenic population lays the groundwork for this model to be used in the identification of proteomic or small non-coding RNA therapeutic targets for the eradication of this critical cellular population. This is significant, as it provides a potential route to limit development of aggressive disease and thus improve survival rates.