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      Retinoic acid and TGF-β signalling cooperate to overcome MYCN-induced retinoid resistance

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          Abstract

          Background

          Retinoid therapy is widely employed in clinical oncology to differentiate malignant cells into their more benign counterparts. However, certain high-risk cohorts, such as patients with MYCN-amplified neuroblastoma, are innately resistant to retinoid therapy. Therefore, we employed a precision medicine approach to globally profile the retinoid signalling response and to determine how an excess of cellular MYCN antagonises these signalling events to prevent differentiation and confer resistance.

          Methods

          We applied RNA sequencing (RNA-seq) and interaction proteomics coupled with network-based systems level analysis to identify targetable vulnerabilities of MYCN-mediated retinoid resistance. We altered MYCN expression levels in a MYCN-inducible neuroblastoma cell line to facilitate or block retinoic acid (RA)-mediated neuronal differentiation. The relevance of differentially expressed genes and transcriptional regulators for neuroblastoma outcome were then confirmed using existing patient microarray datasets.

          Results

          We determined the signalling networks through which RA mediates neuroblastoma differentiation and the inhibitory perturbations to these networks upon MYCN overexpression. We revealed opposing regulation of RA and MYCN on a number of differentiation-relevant genes, including LMO4, CYP26A1, ASCL1, RET, FZD7 and DKK1. Furthermore, we revealed a broad network of transcriptional regulators involved in regulating retinoid responsiveness, such as Neurotrophin, PI3K, Wnt and MAPK, and epigenetic signalling. Of these regulators, we functionally confirmed that MYCN-driven inhibition of transforming growth factor beta (TGF-β) signalling is a vulnerable node of the MYCN network and that multiple levels of cross-talk exist between MYCN and TGF-β. Co-targeting of the retinoic acid and TGF-β pathways, through RA and kartogenin (KGN; a TGF-β signalling activating small molecule) combination treatment, induced the loss of viability of MYCN-amplified retinoid-resistant neuroblastoma cells.

          Conclusions

          Our approach provides a powerful precision oncology tool for identifying the driving signalling networks for malignancies not primarily driven by somatic mutations, such as paediatric cancers. By applying global omics approaches to the signalling networks regulating neuroblastoma differentiation and stemness, we have determined the pathways involved in the MYCN-mediated retinoid resistance, with TGF-β signalling being a key regulator. These findings revealed a number of combination treatments likely to improve clinical response to retinoid therapy, including co-treatment with retinoids and KGN, which may prove valuable in the treatment of high-risk MYCN-amplified neuroblastoma.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s13073-017-0407-3) contains supplementary material, which is available to authorized users.

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          Most cited references86

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          Recent advances in neuroblastoma.

          John Maris (2010)
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            Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.

            Neuroblastoma is a childhood tumour of the peripheral sympathetic nervous system. The pathogenesis has for a long time been quite enigmatic, as only very few gene defects were identified in this often lethal tumour. Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%). Here we present a whole-genome sequence analysis of 87 neuroblastoma of all stages. Few recurrent amino-acid-changing mutations were found. In contrast, analysis of structural defects identified a local shredding of chromosomes, known as chromothripsis, in 18% of high-stage neuroblastoma. These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization. In addition, ATRX, TIAM1 and a series of regulators of the Rac/Rho pathway were mutated, further implicating defects in neuritogenesis in neuroblastoma. Most tumours with defects in these genes were aggressive high-stage neuroblastomas, but did not carry MYCN amplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours.
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              A stem cell-based approach to cartilage repair.

              Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.
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                Author and article information

                Contributors
                duffy@whitney.ufl.edu
                Journal
                Genome Med
                Genome Med
                Genome Medicine
                BioMed Central (London )
                1756-994X
                10 February 2017
                10 February 2017
                2017
                : 9
                : 15
                Affiliations
                [1 ]ISNI 0000 0001 0768 2743, GRID grid.7886.1, Systems Biology Ireland, , University College Dublin, ; Belfield, Dublin 4 Ireland
                [2 ]ISNI 0000 0001 0768 2743, GRID grid.7886.1, , Conway Institute of Biomolecular & Biomedical Research, University College Dublin, ; Belfield, Dublin 4 Ireland
                [3 ]ISNI 0000 0001 0768 2743, GRID grid.7886.1, School of Medicine, , University College Dublin, ; Belfield, Dublin 4 Ireland
                [4 ]The Whitney Laboratory for Marine Bioscience and Sea Turtle Hospital, University of Florida, St. Augustine, Florida 32080 USA
                [5 ]ISNI 0000 0004 0495 846X, GRID grid.4709.a, , European Molecular Biology Laboratory (EMBL), ; Meyerhofstraße 1, 69117 Heidelberg, Germany
                [6 ]ISNI 0000 0001 0658 7699, GRID grid.9811.1, Present address: Department of Biology, , University of Konstanz, ; Konstanz, Germany
                [7 ]ISNI 0000 0004 0400 1852, GRID grid.6324.3, , VTT Technical Research Centre of Finland, ; Tietotie 2, FI-02044 VTT, Espoo, Finland
                Article
                407
                10.1186/s13073-017-0407-3
                5303304
                28187790
                249118b1-78de-42f7-a3cf-3fc8886480dd
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 29 June 2016
                : 20 January 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001602, Science Foundation Ireland;
                Award ID: 06/CE/B1129
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100004963, Seventh Framework Programme;
                Award ID: FP7-HEALTH-2010-259348-2
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2017

                Molecular medicine
                neuroblastoma,kartogenin (kgn),repsox,myc (c-myc),differentiation,mrna sequencing (mrna-seq),chip sequencing (chip-seq),transforming growth factor beta (tgf-β) signalling,interaction proteomics,precision medicine,genome medicine,wnt β-catenin signalling,cancer,systems medicine,neuronal differentiation,differentiation therapy

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