9 results on '"Stroeken P"'
Search Results
2. Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors.
- Author
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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
- Full Text
- View/download PDF
3. A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma.
- Author
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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, and van Nes J
- Subjects
- Adrenergic Neurons metabolism, Cell Line, Tumor, Epigenesis, Genetic, Feedback, Physiological, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Mesenchymal Stem Cells metabolism, Neuroblastoma metabolism, Receptor, Notch3 genetics, Receptor, Notch3 metabolism, Adrenergic Neurons pathology, Cellular Reprogramming genetics, Mesenchymal Stem Cells pathology, Neuroblastoma pathology, Receptor, Notch3 physiology
- 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.
- Published
- 2019
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- View/download PDF
4. FOXO3a is a major target of inactivation by PI3K/AKT signaling in aggressive neuroblastoma.
- Author
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Santo EE, Stroeken P, Sluis PV, Koster J, Versteeg R, and Westerhout EM
- Subjects
- Apoptosis drug effects, Cell Line, Tumor, Forkhead Box Protein O3, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Furans pharmacology, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Neuroblastoma genetics, Neuroblastoma mortality, Neurons cytology, Neurons drug effects, Neurons metabolism, Phosphatidylinositol 3-Kinases genetics, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation drug effects, Prognosis, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt genetics, Pyridines pharmacology, Pyrimidines pharmacology, Survival Rate, Forkhead Transcription Factors antagonists & inhibitors, Neuroblastoma pathology, Phosphatidylinositol 3-Kinases metabolism, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction
- Abstract
Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low-stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late-stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Furthermore, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma., (©2013 AACR.)
- Published
- 2013
- Full Text
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5. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes.
- Author
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Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, Hamdi M, van Nes J, Westerman BA, van Arkel J, Ebus ME, Haneveld F, Lakeman A, Schild L, Molenaar P, Stroeken P, van Noesel MM, Ora I, Santo EE, Caron HN, Westerhout EM, and Versteeg R
- Subjects
- Aging genetics, Cluster Analysis, DNA Helicases genetics, DNA Mutational Analysis, Gene Expression Regulation, Neoplastic, Genome, Human genetics, Growth Cones metabolism, Growth Cones pathology, Guanine Nucleotide Exchange Factors genetics, Humans, Mutation, Neoplasm Staging, Neuroblastoma diagnosis, Neuroblastoma metabolism, Nuclear Proteins genetics, Prognosis, T-Lymphoma Invasion and Metastasis-inducing Protein 1, X-linked Nuclear Protein, rac GTP-Binding Proteins metabolism, rho GTP-Binding Proteins metabolism, Chromosomes, Human genetics, Neurites metabolism, Neuroblastoma genetics, Neuroblastoma pathology
- 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. 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.
- Published
- 2012
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6. Long-term trends in survival of a declining population: the case of the little owl (Athene noctua) in the Netherlands.
- Author
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Le Gouar PJ, Schekkerman H, van der Jeugd HP, Boele A, van Harxen R, Fuchs P, Stroeken P, and van Noordwijk AJ
- Subjects
- Animals, Conservation of Natural Resources, Ecosystem, Endangered Species, Models, Biological, Netherlands, Population Density, Population Dynamics, Strigiformes physiology
- Abstract
The little owl (Athene noctua) has declined significantly in many parts of Europe, including the Netherlands. To understand the demographic mechanisms underlying their decline, we analysed all available Dutch little owl ringing data. The data set spanned 35 years, and included more than 24,000 ringed owls, allowing detailed estimation of survival rates through multi-state capture-recapture modelling taking dispersal into account. We investigated geographical and temporal variation in age-specific survival rates and linked annual survival estimates to population growth rate in corresponding years, as well as to environmental covariates. The best model for estimating survival assumed time effects on both juvenile and adult survival rates, with average annual survival estimated at 0.258 (SE = 0.047) and 0.753 (SE = 0.019), respectively. Juvenile survival rates decreased with time whereas adult survival rates fluctuated regularly among years, low survival occurring about every 4 years. Years when the population declined were associated with low juvenile survival. More than 60% of the variation in juvenile survival was explained by the increase in road traffic intensity or in average temperature in spring, but these correlations rather reflect a gradual decrease in juvenile survival coinciding with long-term global change than direct causal effects. Surprisingly, vole dynamics did not explain the cyclic dynamics of adult survival rate. Instead, dry and cold years led to low adult survival rates. Low juvenile survival rates, that limit recruitment of first-year breeders, and the regular occurrence of years with poor adult survival, were the most important determinants of the population decline of the little owl.
- Published
- 2011
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7. Cytoplasmic domain mutants of beta1 integrin, expressed in beta 1-knockout lymphoma cells, have distinct effects on adhesion, invasion and metastasis.
- Author
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Stroeken PJ, van Rijthoven EA, Boer E, Geerts D, and Roos E
- Subjects
- Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Bone Marrow Cells, CD18 Antigens genetics, CD18 Antigens metabolism, Carrier Proteins metabolism, Cell Adhesion genetics, Cell Line, Fibronectins metabolism, Integrin beta1 metabolism, Integrin beta1 physiology, Liver Neoplasms pathology, Liver Neoplasms secondary, Lymphoma, T-Cell pathology, Mice, Mice, Inbred DBA, Mice, Knockout, Molecular Sequence Data, Muscle Neoplasms pathology, Muscle Neoplasms secondary, Muscle, Skeletal pathology, Neoplasm Transplantation, Recombinant Fusion Proteins physiology, Splenic Neoplasms pathology, Splenic Neoplasms secondary, Stromal Cells, Transfection, Tumor Cells, Cultured, Cell Movement genetics, Cytoplasm metabolism, Integrin beta1 biosynthesis, Integrin beta1 genetics, Intracellular Signaling Peptides and Proteins, Lymphoma, T-Cell genetics, Lymphoma, T-Cell metabolism, Membrane Proteins, Mutation
- Abstract
Structural requirements for beta 1 integrin cytoplasmic domain functions in adhesion, migration and signaling have been studied mainly for fibroblasts in vitro. The relevance for beta 1-dependent in vivo migration of lymphoid cells has not been assessed. To study this, we transfected beta 1 mutants into beta 1-deficient double knockout (DKO) ESb lymphoma cells, and tested the capacity of the cells to metastasize to liver and spleen. This was compared to alpha 4 beta 1-dependent invasion into cell monolayers in vitro and Mn2+-induced adhesion to fibronectin. Deletion of the five C-terminal residues or mutation of both threonines T788 and T789 to alanines blocked invasion and metastasis and greatly reduced adhesion, in line with known in vitro effects. However, mutations of the NPXY motif tyrosines had unexpected consequences. A Y783F mutation had no effect at all, but a Y783,795F double mutation strongly reduced Mn2+-induced adhesion, whereas it had limited effects on invasion and metastasis. Furthermore, cells expressing a beta 1 beta 2 chimeric subunit, which contains phenylalanines in the NPXY/F motifs, adhered poorly but invasion and metastasis was fully restored to the same levels as for cells expressing wild-type beta 1. We conclude that part of the functions of the beta 1 cytoplasmic domain that are required for adhesion are not essential for beta 1-dependent invasion and metastasis.
- Published
- 2000
- Full Text
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8. Targeted disruption of the beta1 integrin gene in a lymphoma cell line greatly reduces metastatic capacity.
- Author
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Stroeken PJ, van Rijthoven EA, van der Valk MA, and Roos E
- Subjects
- Alleles, Animals, Cell Adhesion physiology, Fibronectins metabolism, Genetic Therapy, Integrin alpha4beta1, Integrin beta1 metabolism, Integrins genetics, Integrins metabolism, Laminin metabolism, Liver Neoplasms, Experimental secondary, Lymphoma, T-Cell therapy, Mice, Mice, Inbred DBA, Mice, Knockout, Phenotype, Receptors, Lymphocyte Homing genetics, Receptors, Lymphocyte Homing metabolism, Splenic Neoplasms secondary, Tumor Cells, Cultured, Vascular Cell Adhesion Molecule-1 metabolism, Integrin beta1 genetics, Lymphoma, T-Cell genetics, Lymphoma, T-Cell pathology
- Abstract
Integrins have been implicated in tumor metastasis. To investigate this, we generated beta1 integrin-negative double knockout (DKO) mutants of the highly metastatic ESb murine T-lymphoma cell line. The in vivo growth capacity of the mutants, which had lost alpha4beta1 and alpha6beta1 expression, was not altered, but their metastatic capacity was greatly reduced. Tail vein injection of 10(4) ESb and single-knockout cells led to death of all animals within 9-11 days. In contrast, only one-half of the animals injected with 10(4) DKO cells died, but much later, after 20-60 days. The other one-half remained disease-free for up to 100 days. Whereas ESb and single-knockout cells disseminated predominantly to liver and spleen, metastasis of DKO cells to these organs was rare, even after this prolonged period. Instead, skeletal muscles were invaded extensively. Metastatic capacity was largely restored in a DKO clone, which had been transfected with beta1 cDNA and expressed beta1 at similar levels as ESb cells. We conclude that beta1 integrins are essential for efficient liver and spleen colonization by the ESb lymphoma.
- Published
- 1998
9. Targeted disruption of CD44 in MDAY-D2 lymphosarcoma cells has no effect on subcutaneous growth or metastatic capacity.
- Author
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Driessens MH, Stroeken PJ, Rodriguez Erena NF, van der Valk MA, van Rijthoven EA, and Roos E
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- Animals, Base Sequence, Cell Adhesion physiology, Cell Division physiology, Enzymes, Immobilized metabolism, Hyaluronic Acid metabolism, Injections, Subcutaneous, Integrins biosynthesis, Mice, Molecular Sequence Data, Mutation physiology, Tumor Cells, Cultured cytology, Hyaluronan Receptors physiology, Lymphoma, Non-Hodgkin pathology, Neoplasm Metastasis pathology
- Abstract
CD44 splice variants have been shown to be involved in metastasis of carcinomas. In addition, the standard form of CD44 has been implicated in metastasis, particularly of melanomas and lymphomas. To investigate this, we have generated a CD44-negative mutant of the highly metastatic murine MDAY-D2 lymphosarcoma. The two CD44 alleles of this diploid cell line were sequentially disrupted by homologous recombination, using isogenic CD44 genomic constructs interrupted by a neomycin or hygromycin resistance-conferring gene. The resulting double knockout (DKO) cells had completely lost the capacity to bind to immobilized hyaluronic acid, but did not differ from MDAY-D2 cells in integrin expression or in vitro growth. Subcutaneous (s.c.) growth potential and metastatic capacity of MDAY-D2 and DKO cells were assessed by s.c. and i.v. injection of the lowest cell dose (10(3) or 10(4), respectively) that gave rise to tumor formation by MDAY-D2 cells in approximately 100% of the mice. Quite unexpectedly, we observed no difference at all in either s.c. growth rate or local invasion into surrounding tissues between MDAY-D2 cells and the CD44-negative DKO cells. Also hematogenous metastasis formation upon i.v. injection was similar: both parental and DKO cells metastasized extensively to the spleen, liver, and bone marrow. We conclude that, at least for these MDAY-D2 lymphosarcoma cells, the standard form of CD44 is dispensable for tumor growth and metastasis. Our results show that targeted disruption of genes in tumor cells is a feasible approach to study their role in tumorigenesis and metastasis.
- Published
- 1995
- Full Text
- View/download PDF
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