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.

Integrated Analysis to Study the Relationship between Tumor-Associated Selenoproteins: Focus on Prostate Cancer

“…On the other hand, DIO1 and DIO2 are located on the plasma membrane and ER, respectively, and are part of the iodothyronine deiodinase family and involved in regulating the activity of thyroid hormones by deiodination reactions [61]. DIO2 was found to be highly expressed in mesothelioma cell lines [70], and its inhibition resulted in the suppressed expression of prostate specific antigen (PSA) in prostate cancer, thus representing a potential approach to overcoming castration resistance [71]. Moreover, in prostate cancer, MYC activity was correlated with dysregulation of the PI3K/AKT/mTOR pathway, which induced cellular survival.…”

Transcription Factors in Cancer Development and Therapy

“…The self-renewal and stemness properties of the CSCs are controlled by the same pathways, including Notch, Hedgehog and Wnt, and TFs such as OCT4, SOX2, and NANOG, as in embryonic stem (ES) cells [62]. The induction of stemness TFs in cancers defines poor clinical outcomes and treatment resistance [63], promoting lineage plasticity leading to chemoresistance [64,65]. Both HIF-1α and HIF-2α are essential for CSC maintenance [66,67] and are required for different functions.…”

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

“…As a consequence of all these events, NANOG activates its own distinct transcriptional programme and engage other transcription regulators such as MYC, leading to acquisition of a castration-resistant stem cell-like state [571]. It is not surprising that prostate cancers highly expressing pluripotential transcription factors, such as NANOG, OCT4, and SOX2, more rapidly develop castration resistance and are associated with a poor outcome [572].…”