Journal article
The induction of core pluripotency master regulators in cancers defines poor clinical outcomes and treatment resistance
- 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 status:
- Published
- Peer review status:
- Peer reviewed
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- Publisher copy:
- 10.1038/s41388-019-0712-y
Authors
- Publisher:
- Springer Nature
- Journal:
- Oncogene More from this journal
- Volume:
- 38
- Pages:
- 4412–4424
- Publication date:
- 2019-02-11
- Acceptance date:
- 2019-01-16
- DOI:
- EISSN:
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1476-5594
- ISSN:
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0950-9232
- Pmid:
-
30742096
- Language:
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English
- Pubs id:
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pubs:971397
- UUID:
-
uuid:894eb780-aaaf-4b40-8769-9d6133a44f82
- Local pid:
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pubs:971397
- Source identifiers:
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971397
- Deposit date:
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2019-02-13
- ARK identifier:
Terms of use
- Copyright holder:
- Hepburn et al
- Copyright date:
- 2019
- Notes:
- © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. A Correction to this article is available at https://www.nature.com/articles/s41388-019-0826-2
- Licence:
- CC Attribution (CC BY)
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