W.J. van Nes PhD publications

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Publications PhD W.J. van Nes

Position
Research Associate
Main activities
Research
Specialisation
Molecular biology of cancer
Focus of research

Intra-tumour heterogeneity, lineage plasticity and drug resistance in neuroblastoma

In many tumour types, primary tumours respond to therapy by complete clinical remission, but ultimately relapse as therapy-resistant and lethal disease. My aim is to elucidate this enigmatic process and to devise new treatment options to prevent resistance and relapse. I focus on phenotypic tumour cell heterogeneity, the lineage plasticity of these cell types and their drug-resistance to understand the cellular and molecular mechanism(s) of relapse. My ultimate aim is to eradicate these therapy-resistant cells to prevent relapse and improve patient survival.

With my research group, I have developed a model system of lineage heterogeneity and cellular plasticity to study drug-resistance and relapse of neuroblastoma. We have identified that each neuroblastoma includes two phenotypically divergent tumour cell types with mesenchymal- (MES-type) and adrenergic (ADRN-type) lineage fates, respectively (van Groningen et al., Nature Genetics, 2017). MES and ADRN cell types have been extensively characterized for 1) mRNA expression, 2) the chromatin landscape of super-enhancers, 3) drug-resistance, 4) lineage identity and 5) transdifferentiation induced by lineage transcription factors (TFs).

 

Neuroblastoma includes MES and ADRN tumour cells

We study five isogenic pairs of MES and ADRN cell lines, with each pair derived from the tumour of a single patient. MES and ADRN cell lines shared identical genetic defects, but have highly divergent phenotypes and mRNA expression profiles. The MES-type cells expressed mesenchymal marker genes, were highly migratory and showed lamellipodia. In contrast, the ADRN-type cells were not migratory and expressed adrenergic marker genes, e.g. from the adrenalin-synthesis route (DBH, TH). Importantly, MES and ADRN cells can spontaneously transdifferentiate into one another, both in vitro and in vivo.

We characterized the chromatin landscape of MES and ADRN cells for H3K27ac and identified two sets of ~300 super-enhancers that were unique to either cell type. The MES-specific super-enhancers associated with MES-TFs, while ADRN-specific super-enhancers associated with ADRN TFs. These distinct sets of super-enhancer associated TFs constituted the core regulatory circuitries for each cell type and are proposed to determine lineage-identity. Indeed, overexpression of MES TFs in ADRN neuroblastoma cells reprogrammed ADRN cells towards the MES lineage (van Groningen et al., Nature Genetics, 2017; van Groningen et al., Nature Communications, 2019). This transition was accompanied by downregulation of ADRN super-enhancers and ADRN TFs while MES super-enhancers and MES TFs were induced. These data show that a core set of TFs can impose lineage identity in neuroblastoma.

 

Clinical relevance of MES and ADRN cells

We tested the sensitivity of MES and ADRN cells to chemotherapeutic drugs used in the clinical management of neuroblastoma and found that MES cells are chemo-resistant as compared to ADRN cells (van Groningen et al., Nature Genetics, 2017). In primary human neuroblastoma, we identified a minor population of MES cells. Analysis of pairs of pre- and post-chemotherapy biopsies revealed an enrichment of MES cells, suggesting selective pressure of therapy. Also, some relapse tumours predominantly consisted of MES cells. These data support a model in which a minor population of MES cells exists in primary neuroblastoma. This population can enrich after chemotherapy and may give rise to relapse.

We currently investigate the heterogeneity and plasticity of the divergent neuroblastoma cell types and study their contribution to relapses. We use combinations of single-cell RNA sequencing, bio-informatics, CRISPR-based cell lineage reporters and in vivo relapse models to identify the full spectrum and the dynamics of neuroblastoma cell types. New combinations of cell-type specific drugs are tested to prevent relapse and improve survival. 

 

Research team

Johan van Nes, PhD, group leader

Luciano Rago, PhD, post-doc

Nurdan Akogul, technician

Alvin Chan, technician

 

Tim van Groningen, PhD received his PhD from the University of Amsterdam (d.d. January 22nd, 2020) for his work described in the thesis 'Intra-tumor heterogeneity and lineage plasticity in neuroblastoma' (promotor Prof. R. Versteeg, co-promotor and daily supervisor Johan van Nes, PhD). 

Amsterdam UMC Research Institutes
AMC departments
All publications

2021

  • Gartlgruber Moritz, Sharma Ashwini Kumar, Quintero Andrés, Dreidax Daniel, Jansky Selina, Park Young-Gyu, Kreth Sina, Meder Johanna, Doncevic Daria, Saary Paul, Toprak Umut H., Ishaque Naveed, Afanasyeva Elena, Wecht Elisa, Koster Jan, Versteeg Rogier, Grünewald Thomas G. P., Jones David T. W., Pfister Stefan M., Henrich Kai-Oliver, van Nes Johan, Herrmann Carl, Westermann Frank Super enhancers define regulatory subtypes and cell identity in neuroblastoma Nature Cancer 2021;2 (1):114-128

2020

  • van Groningen Tim Intra-tumor heterogeneity and lineage plasticity in neuroblastoma 2020. 191p. ISBN 9789463756617. [UvA Dissertations Online] University of Amsterdam. (Supervisor: Versteeg R.; Co-supervisor: van Nes W. J.)

2019

  • 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 Nature communications 2019;10 (1):1530 [PubMed]
  • Verly I. R. N., Leen R., Meinsma J. R., Hooijer G. K. J., Savci-Heijink C. D., van Nes J., Broekmans M., Wanders R. J. A., van Kuilenburg A. B. P., Tytgat G. A. M. Catecholamine excretion profiles identify clinical subgroups of neuroblastoma patients European journal of cancer (Oxford, England 2019;111:21-29 [PubMed]
  • van Wezel Esther M. , van Zogchel Lieke M. J. , van Wijk Jalenka, Timmerman Ilse, Vo Ngoc-Kim, Zappeij-Kannegieter Lily, deCarolis Boris, Simon Thorsten, van Noesel Max, Molenaar Jan J. , van Groningen Tim, Versteeg Rogier, Caron Huib N. , van der Schoot C. Ellen, Koster Jan, van Nes Johan, Tytgat Godelieve Mesenchymal Neuroblastoma Cells Are Undetected by Current mRNA Marker Panels: The Development of a Specific Neuroblastoma Mesenchymal Minimal Residual Disease Panel JCO Precision Oncology 2019

2018

  • Decaesteker Bieke, Denecker Geertrui, van Neste Christophe, Dolman Emmy M., van Loocke Wouter, Gartlgruber Moritz, Nunes Carolina, de Vloed Fanny, Depuydt Pauline, Verboom Karen, Rombaut Dries, Loontiens Siebe, de Wyn Jolien, Kholosy Waleed M., Koopmans Bianca, Essing Anke H. W., Herrmann Carl, Dreidax Daniel, Durinck Kaat, Deforce Dieter, van Nieuwerburgh Filip, Henssen Anton, Versteeg Rogier, Boeva Valentina, Schleiermacher Gudrun, van Nes Johan, Mestdagh Pieter, Vanhauwaert Suzanne, Schulte Johannes H., Westermann Frank, Molenaar Jan J., de Preter Katleen, Speleman Frank TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets Nature communications 2018;9 (1):4866 [PubMed]

2017

  • van Groningen Tim, Koster Jan, Valentijn Linda J., Zwijnenburg Danny A., Akogul Nurdan, Hasselt Nancy E., Broekmans Marloes, Haneveld Franciska, Nowakowska Natalia E., Bras Johannes, van Noesel Carel J. M., Jongejan Aldo, van Kampen Antoine H., Koster Linda, Baas Frank, van Dijk-Kerkhoven Lianne, Huizer-Smit Margriet, Lecca Maria C., Chan Alvin, Lakeman Arjan, Molenaar Piet, Volckmann Richard, Westerhout Ellen M., Hamdi Mohamed, van Sluis Peter G., Ebus Marli E., Molenaar Jan J., Tytgat Godelieve A., Westerman Bart A., van Nes Johan, Versteeg Rogier Neuroblastoma is composed of two super-enhancer-associated differentiation states Nature genetics 2017;49 (8):1261-1266 [PubMed]

2013

  • van Nes Johan, Chan Alvin, van Groningen Tim, van Sluis Peter, Koster Jan, Versteeg Rogier A NOTCH3 transcriptional module induces cell motility in neuroblastoma Clinical cancer research 2013;19 (13):3485-3494 [PubMed]

2012

  • Valentijn Linda J., Koster Jan, Haneveld Franciska, Aissa Rachida Ait, van Sluis Peter, Broekmans Marloes E. C., Molenaar Jan J., van Nes Johan, Versteeg Rogier Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification Proceedings of the National Academy of Sciences of the United States of America 2012;109 (47):19190-19195 [PubMed]
  • Molenaar Jan J., Domingo-Fernández Raquel, Ebus Marli E., Lindner Sven, Koster Jan, Drabek Ksenija, Mestdagh Pieter, van Sluis Peter, Valentijn Linda J., van Nes Johan, Broekmans Marloes, Haneveld Franciska, Volckmann Richard, Bray Isabella, Heukamp Lukas, Sprüssel Annika, Thor Theresa, Kieckbusch Kristina, Klein-Hitpass Ludger, Fischer Matthias, Vandesompele Jo, Schramm Alexander, van Noesel Max M., Varesio Luigi, Speleman Frank, Eggert Angelika, Stallings Raymond L., Caron Huib N., Versteeg Rogier, Schulte Johannes H. LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression Nature genetics 2012;44 (11):1199-1206 [PubMed]
  • Molenaar Jan J., Koster Jan, Zwijnenburg Danny A., van Sluis Peter, Valentijn Linda J., van der Ploeg Ida, Hamdi Mohamed, van Nes Johan, Westerman Bart A., van Arkel Jennemiek, Ebus Marli E., Haneveld Franciska, Lakeman Arjan, Schild Linda, Molenaar Piet, Stroeken Peter, van Noesel Max M., Ora Ingrid, Santo Evan E., Caron Huib N., Westerhout Ellen M., Versteeg Rogier Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes Nature 2012;483 (7391):589-U107 [PubMed]

2009

  • Young Teddy, Rowland Jennifer Elizabeth, van de Ven Cesca, Bialecka Monika, Novoa Ana, Carapuco Marta, van Nes Johan, de Graaff Wim, Duluc Isabelle, Freund Jean-Noël, Beck Felix, Mallo Moises, Deschamps Jacqueline Cdx and Hox genes differentially regulate posterior axial growth in mammalian embryos Developmental cell 2009;17 (4):516-526 [PubMed]

2006

  • van Nes Johan, de Graaff Wim, Lebrin Franck, Gerhard Markus, Beck Felix, Deschamps Jacqueline The Cdx4 mutation affects axial development and reveals an essential role of Cdx genes in the ontogenesis of the placental labyrinth in mice Development (Cambridge, England) 2006;133 (3):419-428 [PubMed]

2005

  • Deschamps Jacqueline, van Nes Johan Developmental regulation of the Hox genes during axial morphogenesis in the mouse Development (Cambridge, England) 2005;132 (13):2931-2942 [PubMed]

2004

  • Megens Hendrik-Jan, van Nes W. Johan, van Moorsel Coline H. M., Pierce Naomi E., de Jong Rienk Molecular phylogeny of the Oriental butterfly genus Arhopala (Lycaenidae, Theclinae) inferred from mitochondrial and nuclear genes Systematic Entomology 2004;29 (1):115-131

1990

  • Remeijer Lies, van Rij Gabriel, Beekhuis W. Houdijn, Polak Bettine C. P., van Nes Johan Deep Corneal Stromal Opacities in Long-term Contact Lens Wear Ophthalmology 1990;97 (3):281-285 [PubMed]
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