The induction of core pluripotency master regulators in cancers defines poor clinical outcomes and treatment resistance.

Autor: Hepburn AC; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. anastasia.hepburn@newcastle.ac.uk., Steele RE; Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer, Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, BT9 7AE, UK., Veeratterapillay R; Department of Urology, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN, UK., Wilson L; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Kounatidou EE; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Barnard A; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Berry P; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Cassidy JR; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Moad M; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., El-Sherif A; Department of Pathology, Royal Victoria Infirmary, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK., Gaughan L; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK., Mills IG; Prostate Cancer UK/Movember Centre of Excellence for Prostate Cancer, Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Belfast, BT9 7AE, UK.; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, OX3 9DU, UK., Robson CN; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. c.n.robson@newcastle.ac.uk., Heer R; Northern Institute for Cancer Research, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. rakesh.heer@newcastle.ac.uk.; Department of Urology, Freeman Hospital, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN, UK. rakesh.heer@newcastle.ac.uk.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2019 May; Vol. 38 (22), pp. 4412-4424. Date of Electronic Publication: 2019 Feb 11.
DOI: 10.1038/s41388-019-0712-y
Abstrakt: Stem cell characteristics have been associated with treatment resistance and poor prognosis across many cancer types. The ability to induce and regulate the pathways that sustain these characteristic hallmarks of lethal cancers in a novel in vitro model would greatly enhance our understanding of cancer progression and treatment resistance. In this work, we present such a model, based simply on applying standard pluripotency/embryonic stem cell media alone. Core pluripotency stem cell master regulators (OCT4, SOX2 and NANOG) along with epithelial-mesenchymal transition (EMT) markers (Snail, Slug, vimentin and N-cadherin) were induced in human prostate, breast, lung, bladder, colorectal, and renal cancer cells. RNA sequencing revealed pathways activated by pluripotency inducing culture that were shared across all cancers examined. These pathways highlight a potential core mechanism of treatment resistance. With a focus on prostate cancer, the culture-based induction of core pluripotent stem cell regulators was shown to promote survival in castrate conditions-mimicking first line treatment resistance with hormonal therapies. This acquired phenotype was shown to be mediated through the upregulation of iodothyronine deiodinase DIO2, a critical modulator of the thyroid hormone signalling pathway. Subsequent inhibition of DIO2 was shown to supress expression of prostate specific antigen, the cardinal clinical biomarker of prostate cancer progression and highlighted a novel target for clinical translation in this otherwise fatal disease. This study identifies a new and widely accessible simple preclinical model to recreate and explore underpinning pathways of lethal disease and treatment resistance.
Databáze: MEDLINE
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