A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Tim van Groningen, Nurdan Akogul, Ellen M. Westerhout, Alvin Chan, Nancy E. Hasselt, Danny A. Zwijnenburg, Marloes Broekmans, Peter Stroeken, Franciska Haneveld, Gerrit K. J. Hooijer, C. Dilara Savci-Heijink, Arjan Lakeman, Richard Volckmann, Peter van Sluis, Linda J. Valentijn, Jan Koster, Rogier Versteeg, Johan van Nes

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number1530
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 2019
Externally publishedYes

Cite this

van Groningen, T., Akogul, N., Westerhout, E. M., Chan, A., Hasselt, N. E., Zwijnenburg, D. A., ... van Nes, J. (2019). A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma. Nature Communications, 10(1), [1530]. https://doi.org/10.1038/s41467-019-09470-w
van Groningen, Tim ; Akogul, Nurdan ; Westerhout, Ellen M. ; Chan, Alvin ; Hasselt, Nancy E. ; Zwijnenburg, Danny A. ; Broekmans, Marloes ; Stroeken, Peter ; Haneveld, Franciska ; Hooijer, Gerrit K. J. ; Savci-Heijink, C. Dilara ; Lakeman, Arjan ; Volckmann, Richard ; van Sluis, Peter ; Valentijn, Linda J. ; Koster, Jan ; Versteeg, Rogier ; van Nes, Johan. / A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma. In: Nature Communications. 2019 ; Vol. 10, No. 1.
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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.",
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van Groningen, T, Akogul, N, Westerhout, EM, Chan, A, Hasselt, NE, Zwijnenburg, DA, Broekmans, M, Stroeken, P, Haneveld, F, Hooijer, GKJ, Savci-Heijink, CD, Lakeman, A, Volckmann, R, van Sluis, P, Valentijn, LJ, Koster, J, Versteeg, R & van Nes, J 2019, 'A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma' Nature Communications, vol. 10, no. 1, 1530. https://doi.org/10.1038/s41467-019-09470-w

A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma. / van Groningen, Tim; Akogul, Nurdan; Westerhout, Ellen M.; Chan, Alvin; Hasselt, Nancy E.; Zwijnenburg, Danny A.; Broekmans, Marloes; Stroeken, Peter; Haneveld, Franciska; Hooijer, Gerrit K. J.; Savci-Heijink, C. Dilara; Lakeman, Arjan; Volckmann, Richard; van Sluis, Peter; Valentijn, Linda J.; Koster, Jan; Versteeg, Rogier; van Nes, Johan.

In: Nature Communications, Vol. 10, No. 1, 1530, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

AU - van Groningen, Tim

AU - Akogul, Nurdan

AU - Westerhout, Ellen M.

AU - Chan, Alvin

AU - Hasselt, Nancy E.

AU - Zwijnenburg, Danny A.

AU - Broekmans, Marloes

AU - Stroeken, Peter

AU - Haneveld, Franciska

AU - Hooijer, Gerrit K. J.

AU - Savci-Heijink, C. Dilara

AU - Lakeman, Arjan

AU - Volckmann, Richard

AU - van Sluis, Peter

AU - Valentijn, Linda J.

AU - Koster, Jan

AU - Versteeg, Rogier

AU - van Nes, Johan

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30948783

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JO - Nature Communications

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