1. A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma
- Author
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Richard Volckmann, Ellen M. Westerhout, C. Dilara Savci-Heijink, Alvin Chan, Tim van Groningen, Gerrit K. J. Hooijer, Linda J. Valentijn, Franciska Haneveld, Peter Stroeken, Arjan Lakeman, Jan Koster, Johan van Nes, Nancy E. Hasselt, Danny A. Zwijnenburg, Marloes Broekmans, Peter van Sluis, Nurdan Akogul, Rogier Versteeg, Graduate School, Oncology, CCA - Cancer biology and immunology, Oncogenomics, and Pathology
- Subjects
Adrenergic Neurons ,0301 basic medicine ,Cell type ,animal structures ,Science ,Notch signaling pathway ,General Physics and Astronomy ,02 engineering and technology ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Epigenesis, Genetic ,Neuroblastoma ,03 medical and health sciences ,Cell Line, Tumor ,Humans ,Epigenetics ,lcsh:Science ,Receptor, Notch3 ,Transcription factor ,Feedback, Physiological ,Regulation of gene expression ,Multidisciplinary ,Gene Expression Profiling ,Transdifferentiation ,Mesenchymal Stem Cells ,General Chemistry ,Cellular Reprogramming ,021001 nanoscience & nanotechnology ,Pediatric cancer ,Cell biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,lcsh:Q ,0210 nano-technology ,Reprogramming - Abstract
Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states., Neuroblastoma includes adrenergic and mesenchymal cell types that can interconvert. Here, the authors show that this transdifferentiation is driven by a NOTCH feedforward loop that allows a swift transition between two semi-stable cellular states.
- Published
- 2019
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