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Lookup NU author(s): Dr Anastasia Hepburn, Laura WilsonORCiD, Evangelia Kounatidou, Amy Barnard, Philip Berry, Dr Mohammad Moad, Dr Amira El-Sherif, Dr Luke GaughanORCiD, Professor Craig Robson, Professor Rakesh Heer
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Hepburn AC, Steele RE, Veeratterapillay R, Wilson L, Kounatidou EE, Barnard A, Berry P, Cassidy JR, Moad M, El-Sherif A, Gaughan L, Mills IG, Robson CN, Heer R
Publication type: Article
Publication status: Published
Journal: Oncogene
Year: 2019
Volume: 38
Pages: 4412-4424
Print publication date: 30/05/2019
Online publication date: 11/02/2019
Acceptance date: 16/01/2019
Date deposited: 15/02/2019
ISSN (print): 0950-9232
ISSN (electronic): 1476-5594
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/s41388-019-0712-y
DOI: 10.1038/s41388-019-0712-y
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