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.
Highlights
One of the most daunting clinical challenges is the management of treatment-resistant cancer that leads to incurable lethal disease
When comparing prostate cancer to ageing prostate controls, benign prostatic hyperplasia (BPH), we demonstrated significant upregulation of OSN (n = 67 cancers, sum OSN score 4.7 ± 2.4 vs n = 34 BPH, sum OSN score 3.03 ± 1.1) (Fig. S2A; t-test, p = 0.0002). This treatment naïve cohort contained locally advanced or metastatic prostate cancers that were subsequently treated with androgen deprivation therapy (ADT) and we showed that 93% of patients co-expressed all three factors (OSN), indicating the co-operative recruitment of master regulators promoting a pluripotent phenotype (Fig. 1a, left and middle panel)
We explored OSN expression in non-muscle-invasive bladder cancer (NMIBC) (Fig. S2B-C), where the clinical problem is the risk of recurrence and in those patients with highgrade tumours the risk of progression to muscle-invasive disease
Summary
One of the most daunting clinical challenges is the management of treatment-resistant cancer that leads to incurable lethal disease. A small number of transcription factors including octamer-binding factor 4 (OCT4/Pou5f1), SRY box-containing factor 2 (SOX2), and NANOG were identified as the master regulators of self-renewal and pluripotency of embryonic stem cells (ESCs) [9]. These factors were subsequently shown to reprogramme somatic cells into induced pluripotent stem cells (iPSCs) [10, 11] and are thought to promote lineage plasticity that allows cancer cells to adapt to growing in distinct sites of the body and to develop resistance to cancer therapy [5, 12, 13]. Describing a new model to induce these factors in vitro, we reveal treatment resistance pathways across common cancers and, as an example in prostate cancer, we uncover a new treatment target for castration-resistant disease, the thyroid hormone (TH) pathway
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