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1. ALK positively regulates MYCN activity through repression of HBP1 expression

Author

Claeys, Shana, Denecker, Geertrui, Durinck, Kaat, Decaesteker, Bieke, Mus, Liselot M., Loontiens, Siebe, Vanhauwaert, Suzanne, Althoff, Kristina, Wigerup, Caroline, Bexell, Daniel, Dolman, Emmy, Henrich, Kai-Oliver, Wehrmann, Lea, Westerhout, Ellen M., Demoulin, Jean-Baptiste, Kumps, Candy, Van Maerken, Tom, Laureys, Genevieve, Van Neste, Christophe, De Wilde, Bram, De Wever, Olivier, Westermann, Frank, Versteeg, Rogier, Molenaar, Jan J., Påhlman, Sven, Schulte, Johannes H., De Preter, Katleen, and Speleman, Frank

Published
2019
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2. FOXO3A-short is a novel regulator of non-oxidative glucose metabolism associated with human longevity

Author

Santo, Evan E., Ribel-Madsen, Rasmus, Stroeken, Peter J., de Boer, Vincent C.J., Hansen, Ninna S., Commandeur, Maaike, Vaag, Allan A., Versteeg, Rogier, Paik, Jihye, Westerhout, Ellen M., Santo, Evan E., Ribel-Madsen, Rasmus, Stroeken, Peter J., de Boer, Vincent C.J., Hansen, Ninna S., Commandeur, Maaike, Vaag, Allan A., Versteeg, Rogier, Paik, Jihye, and Westerhout, Ellen M.

Abstract

Intronic single-nucleotide polymorphisms (SNPs) in FOXO3A are associated with human longevity. Currently, it is unclear how these SNPs alter FOXO3A functionality and human physiology, thereby influencing lifespan. Here, we identify a primate-specific FOXO3A transcriptional isoform, FOXO3A-Short (FOXO3A-S), encoding a major longevity-associated SNP, rs9400239 (C or T), within its 5′ untranslated region. The FOXO3A-S mRNA is highly expressed in the skeletal muscle and has very limited expression in other tissues. We find that the rs9400239 variant influences the stability and functionality of the primarily nuclear protein(s) encoded by the FOXO3A-S mRNA. Assessment of the relationship between the FOXO3A-S polymorphism and peripheral glucose clearance during insulin infusion (Rd clamp) in a cohort of Danish twins revealed that longevity T-allele carriers have markedly faster peripheral glucose clearance rates than normal lifespan C-allele carriers. In vitro experiments in human myotube cultures utilizing overexpression of each allele showed that the C-allele represses glycolysis independently of PI3K signaling, while overexpression of the T-allele represses glycolysis only in a PI3K-inactive background. Supporting this finding inducible knockdown of the FOXO3A-S C-allele in cultured myotubes increases the glycolytic rate. We conclude that the rs9400239 polymorphism acts as a molecular switch which changes the identity of the FOXO3A-S-derived protein(s), which in turn alters the relationship between FOXO3A-S and insulin/PI3K signaling and glycolytic flux in the skeletal muscle. This critical difference endows carriers of the FOXO3A-S T-allele with consistently higher insulin-stimulated peripheral glucose clearance rates, which may contribute to their longer and healthier lifespans.

Published
2023

3. Homo sapiens FOXO3A-short (FOXO3A) mRNA, complete cds.

Author

Santo, Evan E., Ribel‐Madsen, Rasmus, Stroeken, Peter J., de Boer, Vincent, Hansen, Ninna S., Commandeur, Maaike, Vaag, Allan A., Versteeg, Rogier, Paik, Jihye, Westerhout, Ellen M., Santo, Evan E., Ribel‐Madsen, Rasmus, Stroeken, Peter J., de Boer, Vincent, Hansen, Ninna S., Commandeur, Maaike, Vaag, Allan A., Versteeg, Rogier, Paik, Jihye, and Westerhout, Ellen M.

Published
2023

5. DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma

Author

Olsen, Thale Kristin, primary, Dyberg, Cecilia, additional, Embaie, Bethel Tesfai, additional, Alchahin, Adele, additional, Milosevic, Jelena, additional, Ding, Jane, additional, Otte, Jörg, additional, Tümmler, Conny, additional, Hed Myrberg, Ida, additional, Westerhout, Ellen M., additional, Koster, Jan, additional, Versteeg, Rogier, additional, Ding, Han-Fei, additional, Kogner, Per, additional, Johnsen, John Inge, additional, Sykes, David B., additional, and Baryawno, Ninib, additional

Published
2022
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6. Correction: Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors

Author

Westerhout, Ellen M., primary, Hamdi, Mohamed, additional, Stroeken, Peter, additional, Nowakowska, Natalia E., additional, Lakeman, Arjan, additional, van Arkel, Jennemiek, additional, Hasselt, Nancy E., additional, Blejlevens, Boris, additional, Akogul, Nurdan, additional, Haneveld, Franciska, additional, Chan, Alvin, additional, van Sluis, Peter, additional, Zwijnenburg, Danny, additional, Volckmann, Richard, additional, van Noesel, Carel JM, additional, Adameyko, Igor, additional, van Gronigen, Tim, additional, Koster, Jan, additional, Valentijn, Linda J., additional, van Nes, Johan, additional, and Versteeg, Rogier, additional

Published
2022
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7. DHODH is an independent prognostic marker and potent therapeutic target in neuroblastoma

Author

Olsen, Thale Kristin, Dyberg, Cecilia, Embaie, Bethel Tesfai, Alchahin, Adele, Milosevic, Jelena, Ding, Jane, Otte, Jörg, Tümmler, Conny, Myrberg, Ida Hed, Westerhout, Ellen M., Koster, Jan, Versteeg, Rogier, Ding, Han-Fei, Kogner, Per, Johnsen, John Inge, Sykes, David B., Baryawno, Ninib, Olsen, Thale Kristin, Dyberg, Cecilia, Embaie, Bethel Tesfai, Alchahin, Adele, Milosevic, Jelena, Ding, Jane, Otte, Jörg, Tümmler, Conny, Myrberg, Ida Hed, Westerhout, Ellen M., Koster, Jan, Versteeg, Rogier, Ding, Han-Fei, Kogner, Per, Johnsen, John Inge, Sykes, David B., and Baryawno, Ninib

Abstract

Despite intensive therapy, children with high-risk neuroblastoma are at risk of treatment failure. We applied a multiomic system approach to evaluate metabolic vulnerabilities in human neuroblastoma. We combined metabolomics, CRISPR screening, and transcriptomic data across more than 700 solid tumor cell lines and identified dihydroorotate dehydrogenase (DHODH), a critical enzyme in pyrimidine synthesis, as a potential treatment target. Of note, DHODH inhibition is currently under clinical investigation in patients with hematologic malignancies. In neuroblastoma, DHODH expression was identified as an independent risk factor for aggressive disease, and high DHODH levels correlated to worse overall and event-free survival. A subset of tumors with the highest DHODH expression was associated with a dismal prognosis, with a 5-year survival of less than 10%. In xenograft and transgenic neuroblastoma mouse models treated with the DHODH inhibitor brequinar, tumor growth was dramatically reduced, and survival was extended. Furthermore, brequinar treatment was shown to reduce the expression of MYC targets in 3 neuroblastoma models in vivo. A combination of brequinar and temozolomide was curative in the majority of transgenic TH-MYCN neuroblastoma mice, indicating a highly active clinical combination therapy. Overall, DHODH inhibition combined with temozolomide has therapeutic potential in neuroblastoma, and we propose this combination for clinical testing., Thale Kristin Olsen, Cecilia Dyberg, David B Sykes, and Ninib Baryawno contributed equally to this work.

Published
2022
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9. Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors

Author

Westerhout, Ellen M., primary, Hamdi, Mohamed, additional, Stroeken, Peter, additional, Nowakowska, Natalia E., additional, Lakeman, Arjan, additional, van Arkel, Jennemiek, additional, Hasselt, Nancy E., additional, Bleijlevens, Boris, additional, Akogul, Nurdan, additional, Haneveld, Franciska, additional, Chan, Alvin, additional, van Sluis, Peter, additional, Zwijnenburg, Danny, additional, Volckmann, Richard, additional, van Noesel, Carel J.M., additional, Adameyko, Igor, additional, van Groningen, Tim, additional, Koster, Jan, additional, Valentijn, Linda J., additional, van Nes, Johan, additional, and Versteeg, Rogier, additional

Published
2021
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10. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes

Author

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., and Versteeg, Rogier

Subjects
Nucleotide sequencing -- Usage, Immunohistochemistry -- Usage, DNA sequencing -- Usage, Neuroblastoma -- Risk factors -- Genetic aspects -- Prognosis -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

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 (1). Frequently detected gene alterations are limited to MYCN amplification (20%) and ALK activations (7%) (2-5).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 (6). These tumours are associated with a poor outcome. Structural alterations recurrently affected ODZ3, PTPRD and CSMD1, which are involved in neuronal growth cone stabilization (7-9).Inaddition, 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 MYCNamplifications. The genomic landscape of neuroblastoma therefore reveals two novel molecular defects, chromothripsis and neuritogenesis gene alterations, which frequently occur in high-risk tumours., Neuroblastoma have a highly variable clinical outcome, with an excellent prognosis for stage 1 and 2 tumours, but a poor outcome for high-stage tumours. Stage 4S neuroblastoma are metastasized but [...]

Published
2012
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14. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

Author

Lamers Fieke, Schild Linda, Koster Jan, Speleman Frank, Øra Ingrid, Westerhout Ellen M, van Sluis Peter, Versteeg Rogier, Caron Huib N, and Molenaar Jan J

Subjects
Neuroblastoma, BIRC6, DIABLO, Apoptosis, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Methods Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays) and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform (http://r2.amc.nl). BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. Results We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP), that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Conclusion Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma.

Published
2012
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15. A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Author

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

Published
2019
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16. Dendritic cells potently purge latent HIV-1 beyond TCR-stimulation, activating the PI3K-Akt-mTOR pathway

Author

van Montfort, Thijs, primary, van der Sluis, Renée, additional, Darcis, Gilles, additional, Beaty, Doyle, additional, Groen, Kevin, additional, Pasternak, Alexander O., additional, Pollakis, Georgios, additional, Vink, Monique, additional, Westerhout, Ellen M., additional, Hamdi, Mohamed, additional, Bakker, Margreet, additional, van der Putten, Boas, additional, Jurriaans, Suzanne, additional, Prins, Jan H., additional, Jeeninga, Rienk, additional, Thomas, Adri A.M., additional, Speijer, Dave, additional, and Berkhout, Ben, additional

Published
2019
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17. ALK positively regulates MYCN activity through repression of HBP1 expression

Author

Claeys, Shana, primary, Denecker, Geertrui, additional, Durinck, Kaat, additional, Decaesteker, Bieke, additional, Mus, Liselot M., additional, Loontiens, Siebe, additional, Vanhauwaert, Suzanne, additional, Althoff, Kristina, additional, Wigerup, Caroline, additional, Bexell, Daniel, additional, Dolman, Emmy, additional, Henrich, Kai-Oliver, additional, Wehrmann, Lea, additional, Westerhout, Ellen M., additional, Demoulin, Jean-Baptiste, additional, Kumps, Candy, additional, Van Maerken, Tom, additional, Laureys, Genevieve, additional, Van Neste, Christophe, additional, De Wilde, Bram, additional, De Wever, Olivier, additional, Westermann, Frank, additional, Versteeg, Rogier, additional, Molenaar, Jan J., additional, Påhlman, Sven, additional, Schulte, Johannes H., additional, De Preter, Katleen, additional, and Speleman, Frank, additional

Published
2018
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18. Liquid chromatography-tandem mass spectrometric assay for the PI3K/mTOR inhibitor GSK2126458 in mouse plasma and tumor homogenate

Author

Dolman, M. Emmy M, Westerhout, Ellen M., Hamdi, Mohamed, Schellens, Jan H M, Beijnen, Jos H., Sparidans, Rolf W., Sub Clinical Pharmacology, Sub Medicinal Chemistry & Chemical biol., Molecular Pharmacy, Pharmacoepidemiology and Clinical Pharmacology, Sub Clinical Pharmacology, Sub Medicinal Chemistry & Chemical biol., Molecular Pharmacy, Pharmacoepidemiology and Clinical Pharmacology, Oncology, Cancer Center Amsterdam, Amsterdam Public Health, and Human Genetics

Subjects
Spectrometry, Mass, Electrospray Ionization, Electrospray, Bioanalysis, Mouse, Tumor homogenate, Clinical Biochemistry, Pharmaceutical Science, GSK2126458, Analytical Chemistry, Mice, Neuroblastoma, Plasma, chemistry.chemical_compound, Tandem Mass Spectrometry, Neoplasms, Drug Discovery, Animals, Protein precipitation, LC-MS/MS, Acetonitrile, Protein Kinase Inhibitors, Spectroscopy, Phosphoinositide-3 Kinase Inhibitors, Sulfonamides, Chromatography, Elution, TOR Serine-Threonine Kinases, Selected reaction monitoring, Reproducibility of Results, Triple quadrupole mass spectrometer, Dilution, Pyridazines, chemistry, Calibration, Quinolines, Female, Chromatography, Liquid
Abstract

A quantitative bioanalytical liquid chromatography-tandem mass spectrometric (LC-MS/MS) assay for GSK2126458, a dual PI3K/mTOR inhibitor, was developed and validated. Plasma and tumor homogenate samples were pre-treated using protein precipitation with acetonitrile containing dabrafenib as internal standard. After dilution with water, the extract was directly injected into the reversed-phase liquid chromatographic system. The eluate was transferred into the electrospray interface with positive ionization and compounds were detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer. The assay was completely validated for plasma in a 4–4000 ng/ml calibration range with r 2 = 0.9996 ± 0.0003 using double logarithmic calibration ( n = 5). Within-run precisions ( n = 6) were 2.0–5.3% and between-run (3 runs; n = 18) precisions 2.7–5.8%. Accuracies were between 101 and 105% for the whole calibration range. The drug was sufficiently stable under all relevant analytical conditions. Finally, the assay was successfully applied to determine plasma and tumor drug levels after oral administration of GSK2126458 to mice with AMC711T neuroblastoma xenografts.

Published
2015

19. HIV-1 latency in actively dividing human T cell lines

Author

Berkhout Ben, van Gerven Marja L, Westerhout Ellen M, and Jeeninga Rienk E

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background Eradication of HIV-1 from an infected individual cannot be achieved by current drug regimens. Viral reservoirs established early during the infection remain unaffected by anti-retroviral therapy and are able to replenish systemic infection upon interruption of the treatment. Therapeutic targeting of viral latency will require a better understanding of the basic mechanisms underlying the establishment and long-term maintenance of HIV-1 in resting memory CD4 T cells, the most prominent reservoir of transcriptional silent provirus. However, the molecular mechanisms that permit long-term transcriptional control of proviral gene expression in these cells are still not well understood. Exploring the molecular details of viral latency will provide new insights for eventual future therapeutics that aim at viral eradication. Results We set out to develop a new in vitro HIV-1 latency model system using the doxycycline (dox)-inducible HIV-rtTA variant. Stable cell clones were generated with a silent HIV-1 provirus, which can subsequently be activated by dox-addition. Surprisingly, only a minority of the cells was able to induce viral gene expression and a spreading infection, eventhough these experiments were performed with the actively dividing SupT1 T cell line. These latent proviruses are responsive to TNFα treatment and alteration of the DNA methylation status with 5-Azacytidine or genistein, but not responsive to the regular T cell activators PMA and IL2. Follow-up experiments in several T cell lines and with wild-type HIV-1 support these findings. Conclusion We describe the development of a new in vitro model for HIV-1 latency and discuss the advantages of this system. The data suggest that HIV-1 proviral latency is not restricted to resting T cells, but rather an intrinsic property of the virus.

Published
2008
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20. The virion-associated incoming HIV-1 RNA genome is not targeted by RNA interference

Author

Berkhout Ben, ter Brake Olivier, and Westerhout Ellen M

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Abstract Background RNA interference (RNAi) has proven to be a powerful tool to suppress gene expression and can be used as a therapeutic strategy against human pathogenic viruses such as human immunodeficiency virus type 1 (HIV-1). Theoretically, RNAi-mediated inhibition can occur at two points in the replication cycle, upon viral entry before reverse transcription of the RNA genome, and on the newly transcribed viral RNA transcripts. There have been conflicting results on whether RNAi can target the RNA genome of infecting HIV-1 particles. We have addressed this issue with HIV-1-based lentiviral vectors. Results We determined the transduction efficiency of a lentiviral vector, as measured by GFP expressing cells, which reflects the number of successful integration events in a cell line stably expressing shNef. We did not observe a difference in the transduction efficiency comparing lentiviral vectors with or without the Nef target sequence in their genome. The results were similar with particles pseudotyped with either the VSV-G or HIV-1 envelope. Additionally, no reduced transduction efficiencies were observed with multiple other shRNAs targeting the vector genome or with synthetic siNef when transiently transfected prior to transduction. Conclusion Our findings indicate that the incoming HIV-1 RNA genome is not targeted by RNAi, probably due to inaccessibility to the RNAi machinery. Thus, therapeutic RNAi strategies aimed at preventing proviral integration should be targeting cellular receptors or co-factors involved in pre-integration events.

Published
2006
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21. High efficacy of the BCL-2 inhibitor ABT199 (venetoclax) in BCL-2 high-expressing neuroblastoma cell lines and xenografts and rational for combination with MCL-1 inhibition

Author

Bate-Eya, Laurel T., primary, den Hartog, Ilona J.M., additional, van der Ploeg, Ida, additional, Schild, Linda, additional, Koster, Jan, additional, Santo, Evan E., additional, Westerhout, Ellen M., additional, Versteeg, Rogier, additional, Caron, Huib N., additional, Molenaar, Jan J., additional, and Dolman, M. Emmy M., additional

Published
2016
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23. Liquid chromatography-tandem mass spectrometric assay for the PI3K/mTOR inhibitor GSK2126458 in mouse plasma and tumor homogenate

Author

Sub Clinical Pharmacology, Sub Medicinal Chemistry & Chemical biol., Molecular Pharmacy, Pharmacoepidemiology and Clinical Pharmacology, Dolman, M. Emmy M, Westerhout, Ellen M., Hamdi, Mohamed, Schellens, Jan H M, Beijnen, Jos H., Sparidans, Rolf W., Sub Clinical Pharmacology, Sub Medicinal Chemistry & Chemical biol., Molecular Pharmacy, Pharmacoepidemiology and Clinical Pharmacology, Dolman, M. Emmy M, Westerhout, Ellen M., Hamdi, Mohamed, Schellens, Jan H M, Beijnen, Jos H., and Sparidans, Rolf W.

Published
2015

24. Abstract 2980: Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations

Author

Oldridge, Derek A., primary, Eleveld, Thomas F., additional, Bernard, Virginie, additional, Koster, Jan, additional, Daage, Leo C., additional, Diskin, Sharon J., additional, Schild, Linda, additional, Bentahar, Nadia B., additional, Bellini, Angela, additional, Chicard, Mathieu, additional, Lapouble, Eve, additional, Combaret, Valérie, additional, Legoix-Né, Patricia, additional, Michon, Jean, additional, Pugh, Trevor J., additional, Hart, Lori S., additional, Rader, JulieAnn, additional, Attiyeh, Edward F., additional, Wei, Jun S., additional, Zhang, Shile, additional, Naranjo, Arlene, additional, Gastier-Foster, Julie M., additional, Hogarty, Michael D., additional, Smith, Malcolm A., additional, Auvil, Jaime G., additional, Watkins, Thomas B. K., additional, Zwijnenburg, Danny A., additional, Ebus, Marli E., additional, van Sluis, Peter, additional, Hakkert, Anne, additional, van Wezel, Esther, additional, van der Schoot, C. Ellen, additional, Westerhout, Ellen M., additional, Schulte, Johannes H., additional, Tytgat, Godelieve A., additional, Dolman, M. Emmy M., additional, Janoueix-Lerosey, Isabelle, additional, Gerhard, Daniela S., additional, Caron, Huib N., additional, Delattre, Olivier, additional, Khan, Javed, additional, Versteeg, Rogier, additional, Schleiermacher, Gudrun, additional, Maris, John M., additional, and Molenaar, Jan J., additional

Published
2015
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25. Identification of BIRC6 as a novel intervention target for neuroblastoma therapy

Author

Lamers, Fieke, Schild, Linda, Koster, Jan, Speleman, Frank, Øra, Ingrid, Westerhout, Ellen M., van Sluis, Peter, Versteeg, Rogier, Caron, Huib N., Molenaar, Jan J., Lamers, Fieke, Schild, Linda, Koster, Jan, Speleman, Frank, Øra, Ingrid, Westerhout, Ellen M., van Sluis, Peter, Versteeg, Rogier, Caron, Huib N., and Molenaar, Jan J.

Abstract

Background: Neuroblastoma are pediatric tumors of the sympathetic nervous system with a poor prognosis. Apoptosis is often deregulated in cancer cells, but only a few defects in apoptotic routes have been identified in neuroblastoma. Methods: Here we investigated genomic aberrations affecting genes of the intrinsic apoptotic pathway in neuroblastoma. We analyzed DNA profiling data (CGH and SNP arrays) and mRNA expression data of 31 genes of the intrinsic apoptotic pathway in a dataset of 88 neuroblastoma tumors using the R2 bioinformatic platform (http://r2.amc.nl). BIRC6 was selected for further analysis as a tumor driving gene. Knockdown experiments were performed using BIRC6 lentiviral shRNA and phenotype responses were analyzed by Western blot and MTT-assays. In addition, DIABLO levels and interactions were investigated with immunofluorescence and co-immunoprecipitation. Results: We observed frequent gain of the BIRC6 gene on chromosome 2, which resulted in increased mRNA expression. BIRC6 is an inhibitor of apoptosis protein (IAP), that can bind and degrade the cytoplasmic fraction of the pro-apoptotic protein DIABLO. DIABLO mRNA expression was exceptionally high in neuroblastoma but the protein was only detected in the mitochondria. Upon silencing of BIRC6 by shRNA, DIABLO protein levels increased and cells went into apoptosis. Co-immunoprecipitation confirmed direct interaction between DIABLO and BIRC6 in neuroblastoma cell lines. Conclusion: Our findings indicate that BIRC6 may have a potential oncogenic role in neuroblastoma by inactivating cytoplasmic DIABLO. BIRC6 inhibition may therefore provide a means for therapeutic intervention in neuroblastoma.

Published
2012

27. Meta-analysis of Neuroblastomas Reveals a Skewed ALK Mutation Spectrum in Tumors with MYCN Amplification

Author

De Brouwer, Sara, primary, De Preter, Katleen, additional, Kumps, Candy, additional, Zabrocki, Piotr, additional, Porcu, Michaël, additional, Westerhout, Ellen M., additional, Lakeman, Arjan, additional, Vandesompele, Jo, additional, Hoebeeck, Jasmien, additional, Van Maerken, Tom, additional, De Paepe, Anne, additional, Laureys, Geneviève, additional, Schulte, Johannes H., additional, Schramm, Alexander, additional, Van Den Broecke, Caroline, additional, Vermeulen, Joëlle, additional, Van Roy, Nadine, additional, Beiske, Klaus, additional, Renard, Marleen, additional, Noguera, Rosa, additional, Delattre, Olivier, additional, Janoueix-Lerosey, Isabelle, additional, Kogner, Per, additional, Martinsson, Tommy, additional, Nakagawara, Akira, additional, Ohira, Miki, additional, Caron, Huib, additional, Eggert, Angelika, additional, Cools, Jan, additional, Versteeg, Rogier, additional, and Speleman, Frank, additional

Published
2010
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28. Abstract C114: The KidsCancerKinome: Validation of CDK2 as potential drug target in pediatric tumors

Author

Molenaar, Jan J., primary, Westerhout, Ellen M., additional, Boer den, Monique L., additional, Clifford, Steve C., additional, Delattre, Olivier, additional, Geoerger, Birgit, additional, Lanvers, Claudia, additional, Pietsch, Torsten, additional, Serra, Massimo, additional, Shipley, Janet, additional, Vassal, Gilles, additional, Versteeg, Rogier, additional, Verschuur, Arnauld C., additional, and Caron, Huib N., additional

Published
2009
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29. Abstract C115: The KidsCancerKinome: Validation of Aurora kinases as potential drug targets in pediatric tumors

Author

Westerhout, Ellen M., primary, Kool, Marcel, additional, Molenaar, Jan J., additional, Boer den, Monique L., additional, Clifford, Steve C., additional, Delattre, Olivier, additional, Geoerger, Birgit, additional, Lanvers, Claudia, additional, Pietsch, Torsten, additional, Serra, Massimo, additional, Shipley, Janet, additional, Vassal, Gilles, additional, Versteeg, Rogier, additional, Verschuur, Arnauld C., additional, and Caron, Huib N., additional

Published
2009
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34. Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors.

Author

Westerhout EM, Hamdi M, Stroeken P, Nowakowska NE, Lakeman A, van Arkel J, Hasselt NE, Bleijlevens B, Akogul N, Haneveld F, Chan A, van Sluis P, Zwijnenburg D, Volckmann R, van Noesel CJM, Adameyko I, van Groningen T, Koster J, Valentijn LJ, van Nes J, and Versteeg R

Subjects
Cell Line, Tumor, Humans, Neuroblastoma pathology, Anaplastic Lymphoma Kinase antagonists & inhibitors, Neuroblastoma genetics
Abstract

Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase ( ALK ) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors. SIGNIFICANCE: In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell-targeting TRAIL delays tumor relapse., (©2021 American Association for Cancer Research.)

Published
2022
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