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

Lookup NU author(s): Dr Anastasia Hepburn, Laura Wilson, Evangelia Kounatidou, Amy Barnard, Philip Berry, Dr Mohammad Moad, Dr Amira El-Sherif, Dr Luke Gaughan, Professor Craig Robson, Dr Rakesh Heer

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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

Pages: ePub ahead of Print

Online publication date: 11/02/2019

Acceptance date: 16/01/2019

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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