67 results on '"Snaar-Jagalska, B.E."'
Search Results
2. Data from miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression
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Zoni, E., primary, van der Horst, G., primary, van de Merbel, A.F., primary, Chen, L., primary, Rane, J.K., primary, Pelger, R.C.M., primary, Collins, A.T., primary, Visakorpi, T., primary, Snaar-Jagalska, B.E., primary, Maitland, N.J., primary, and van der Pluijm, G., primary
- Published
- 2023
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3. Supplementary Tables S1-S2 from miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression
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Zoni, E., primary, van der Horst, G., primary, van de Merbel, A.F., primary, Chen, L., primary, Rane, J.K., primary, Pelger, R.C.M., primary, Collins, A.T., primary, Visakorpi, T., primary, Snaar-Jagalska, B.E., primary, Maitland, N.J., primary, and van der Pluijm, G., primary
- Published
- 2023
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4. Supplementary Figure Legend from miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression
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Zoni, E., primary, van der Horst, G., primary, van de Merbel, A.F., primary, Chen, L., primary, Rane, J.K., primary, Pelger, R.C.M., primary, Collins, A.T., primary, Visakorpi, T., primary, Snaar-Jagalska, B.E., primary, Maitland, N.J., primary, and van der Pluijm, G., primary
- Published
- 2023
- Full Text
- View/download PDF
5. Establishment of embryonic zebrafish xenograft assays to investigate TGF-β family signaling in human breast cancer progression
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Li, C., Ma, J., Groenewoud, A., Ren, J., Liu, S., Snaar-Jagalska, B.E., Dijke, P. ten, Zi, Z., and Liu, X.
- Published
- 2022
6. Zebrafish models for studying bone tumors
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Groenewoud, A., Kint, M., Snaar-Jagalska, B.E., Cleton-Jansen, A.M., Heymann, D., and Heymann, D.
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biology ,biology.organism_classification ,Zebrafish ,Cell biology - Published
- 2022
7. Single-Molecule Imaging Technique to Study the Dynamic Regulation of GPCR Function at the Plasma Membrane
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Snaar-Jagalska, B.E., primary, Cambi, A., additional, Schmidt, T., additional, and de Keijzer, S., additional
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- 2013
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8. Zebravis tegen kanker: van aquarium tot patiënt
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Snaar-Jagalska, B.E. and Leiden
- Abstract
Oratie uitgesproken door prof.dr. B.E. Snaar-Jagalska bij de aanvaarding van het ambt van hoogleraar op het gebied van Cellulaire Tumorbiologie aan de Universiteit Leiden op maandag 11 december 2017
- Published
- 2017
9. Fish tales: The use of zebrafish xenograft human cancer cell models
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Drabsch, Y., Snaar-Jagalska, B.E., and Dijke, P. ten
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Drug screening ,Embryo ,Xenograft ,Zebrafish ,Cancer - Abstract
Advances in scientific techniques have provided researchers with exceptional new opportunities to identify and monitor changes between different cancer types, during different stages of progression, between individual tumor cells and in the surrounding stroma. The wealth of information that can be obtained from new scientific techniques places additional requirements on the conventional cancer models. New models that could be used to rapidly access the (potential) functional importance of newly identified (epi)genetic and proteomic changes and test the efficacy on emerging (combinatorial) therapies are desperately required. The distinctive characteristics of zebrafish are progressively being applied to create more relevant models of human diseases. Zebrafish embryos provide a powerful tool to develop functional cancer models. This is a tool that can be used from drug discovery and development to assessment of drug toxicity. This review will summarise the use of zebrafish xenograft models to study human cancers, and discuss the benefits and limitations of these models.
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- 2017
10. A Zebrafish Xenograft Model for Studying Human Cancer Stem Cells in distant metastasis and therapy response
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Chen, L., Groenewoud, A., Tulotta, C., Zoni, E., Kruithof-de Julio, M., Horst, G. van der, Pluijm, G. van der, and Snaar-Jagalska, B.E.
- Published
- 2017
11. Generation of Constitutive Active ERK Mutants as Tools for Cancer Research in Zebrafish
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Rian, H., Krens, S.F.G., Spaink, H.P., Snaar-Jagalska, B.E., and Snaar, B.E.
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MAPK/ERK pathway ,0303 health sciences ,Cyclin-dependent kinase 1 ,animal structures ,Article Subject ,biology ,Transgene ,Mutant ,biology.organism_classification ,Molecular biology ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Cancer research ,Ectopic expression ,Kinase activity ,Signal transduction ,Zebrafish ,030304 developmental biology - Abstract
The extracellular-signal-regulated-kinase (ERK) signaling pathway is essential for vertebrate development and is frequently deregulated in human and zebrafish tumors. Previously, we cloned and characterized the zebrafish MAPK gene family and showed that ERK2 is crucial for cell migration and early zebrafish embryogenesis. To further study ERK2 function we generated constitutively active mutant forms of the ERK proteins by introducing conserved point mutations. We validated the enhanced protein activity in vitro by transfection of constructs into zebrafish fibroblast (zf4) cells and demonstrated elevated phosphorylation levels of downstream targets P90RSK and CREB, by ERK2L84P/S162D and ERK2L84P/S162D/D330N specifically. In vivo validation was performed by ectopic expression of corresponding mRNAs in the transgenic zebrafish FGF-ERK2 reporter fish line Tg(Dusp6:d2EGFP). Both mutant ERK2 isoforms induced elevated transgene expression compared to ERK2WT, confirming increased kinase activity in vivo. Phospho-kinomic analysis on peptide microarrays was performed to identify new targets in embryos injected with FGF8 or ERK2L84P/S162D/D330N mRNAs. We detected both FGF8 specific and common signalling targets. Interestingly, with both mRNAs we found increased phosphorylation levels of CDK1, which is critical for proper G2/M phase transition and mitotic entry in proliferation control. These results corroborate that constitutive activation of the ERK2 pathway leads to enhanced, possibly oncogenic, proliferation.
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- 2013
12. UM Cure 2020: New therapies for uveal melanoma
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Roman-Roman, Sergio, primary, Stern, Marc-Henri, additional, Alsafadi, Samar, additional, Jager, Martine J., additional, Dogrusöz, Mehmet, additional, Coupland, Sarah E., additional, Mione, Maria Caterina, additional, Anelli, Viviana, additional, Precazzini, Francesca, additional, Mobuchon, Lenha, additional, Nemati, Fariba, additional, Decaudin, Didier, additional, Rodrigues, Manuel, additional, Lantz, Olivier, additional, Barnhill, Raymond, additional, Piperno-Neumann, Sophie, additional, Cassoux, Nathalie, additional, Desjardins, Laurence, additional, Gezgin, Gulçin, additional, Wierenga, Annemijn, additional, Jochemsen, Aart J., additional, Glinkina, Kseniya A., additional, van der Velden, Pieter A., additional, Nell, Rogier J., additional, Groenewoud, Arwin, additional, Snaar-Jagalska, B.E., additional, Marais, Richard, additional, Mahal, Katharina, additional, Hascoet, Pauline, additional, Kalirai, Helen, additional, Elas, Martyna, additional, Romanowska-Dixon, Bozena, additional, Ruijtenbeek, Rob, additional, van den Heuvel, Dianne, additional, Houkes, Liesbeth, additional, Lebel-Binay, Sophie, additional, Prestat, Antoine, additional, Sengenés, Jennifer, additional, Ryll, Bettina, additional, Valente, André, additional, and Vinolo, Emilie, additional
- Published
- 2018
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13. Automation of Technology for Cancer Research
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Ent, W. van der, Veneman, W.J., Groenewoud, A., Chen, L.P., Tulotta, C., Hogendoorn, P.C.W., Spaink, H.P., Snaar-Jagalska, B.E., and Langenau, D.M.
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Automation ,Microfluidics ,High-throughput ,Robotics ,Zebrafish ,Cancer ,Image analysis - Abstract
Zebrafish embryos can be obtained for research purposes in large numbers at low cost and embryos develop externally in limited space, making them highly suitable for high-throughput cancer studies and drug screens. Non-invasive live imaging of various processes within the larvae is possible due to their transparency during development, and a multitude of available fluorescent transgenic reporter lines. To perform high-throughput studies, handling large amounts of embryos and larvae is required. With such high number of individuals, even minute tasks may become time-consuming and arduous. In this chapter, an overview is given of the developments in the automation of various steps of large scale zebrafish cancer research for discovering important cancer pathways and drugs for the treatment of human disease. The focus lies on various tools developed for cancer cell implantation, embryo handling and sorting, microfluidic systems for imaging and drug treatment, and image acquisition and analysis. Examples will be given of employment of these technologies within the fields of toxicology research and cancer research.
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- 2016
14. Inhibition of signaling between human CXCR4 and zebrafish ligands by the small molecule IT1t impairs the formation of triple-negative breast cancer early metastases in a zebrafish xenograft model
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Tulotta, C., Stefanescu, C., Beletkaia, E., Bussmann, J., Tarbashevich, K., Schmidt, T., and Snaar-Jagalska, B.E.
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Receptors, CXCR4 ,Molecular Sequence Data ,lcsh:Medicine ,Triple Negative Breast Neoplasms ,Metastases ,Ligands ,Triple-negative breast cancer ,lcsh:Pathology ,Animals ,Humans ,Amino Acid Sequence ,Neoplasm Metastasis ,Zebrafish ,CXCR4 ,Sequence Homology, Amino Acid ,IT1t ,Xenograft ,lcsh:R ,CXCL12 ,Disease Models, Animal ,Inter-species crosstalk ,Heterografts ,Female ,lcsh:RB1-214 ,Research Article - Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive and recurrent type of breast carcinoma that is associated with poor patient prognosis. Because of the limited efficacy of current treatments, new therapeutic strategies need to be developed. The CXCR4-CXCL12 chemokine signaling axis guides cell migration in physiological and pathological processes, including breast cancer metastasis. Although targeted therapies to inhibit the CXCR4-CXCL12 axis are under clinical experimentation, still no effective therapeutic approaches have been established to block CXCR4 in TNBC. To unravel the role of the CXCR4-CXCL12 axis in the formation of TNBC early metastases, we used the zebrafish xenograft model. Importantly, we demonstrate that cross-communication between the zebrafish and human ligands and receptors takes place and human tumor cells expressing CXCR4 initiate early metastatic events by sensing zebrafish cognate ligands at the metastatic site. Taking advantage of the conserved intercommunication between human tumor cells and the zebrafish host, we blocked TNBC early metastatic events by chemical and genetic inhibition of CXCR4 signaling. We used IT1t, a potent CXCR4 antagonist, and show for the first time its promising anti-tumor effects. In conclusion, we confirm the validity of the zebrafish as a xenotransplantation model and propose a pharmacological approach to target CXCR4 in TNBC., Summary: CXCR4-expressing human tumor cells respond to zebrafish cognate ligands and initiate metastatic events in a zebrafish xenograft model. The CXCR4 antagonist IT1t has promising tumor inhibitory effects.
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- 2015
15. SYK is a candidate kinase target for the treatment of advanced prostate cancer
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Ghotra, V.P.S., He, S., Horst, G. van der, Nijhoff, S., Bont, H. de, Lekkerkerker, A., Janssen, R., Jenster, G., Leenders, G.J.L.H. van, Hoogland, A., Marije, M., Verhoef, Esther I., Baranski, Madrigal Z., Xiong, J., Water, B. van de, Pluijm, G. van den, Snaar-Jagalska, B.E., Danen, E.H.J., Urology, and Pathology
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Male ,Cancer Research ,Cell ,Syk ,Mice, Nude ,Prostate cancer ,Mice ,SDG 3 - Good Health and Well-being ,In vivo ,Cell Line, Tumor ,medicine ,Gene silencing ,Animals ,Humans ,Syk Kinase ,Molecular Targeted Therapy ,RNA, Small Interfering ,Protein Kinase Inhibitors ,Zebrafish ,Mice, Inbred BALB C ,biology ,business.industry ,Kinase ,CD44 ,Intracellular Signaling Peptides and Proteins ,Cancer ,Prostatic Neoplasms ,hemic and immune systems ,Protein-Tyrosine Kinases ,medicine.disease ,medicine.anatomical_structure ,HEK293 Cells ,Oncology ,biology.protein ,Cancer research ,Heterografts ,business - Abstract
Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2β1 and CD44 were diminished. RNAi-mediated silencing of α2β1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2β1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I–II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer. Cancer Res; 75(1); 230–40. ©2014 AACR.
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- 2015
16. Ewing sarcoma inhibition by disruption of EWSR1-FLI1 transcriptional activity and reactivation of p53
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Ent, W. van der, Jochemsen, A.G., Teunisse, A.F.A.S., Krens, S.F.G., Szuhai, K., Spaink, H.P., Hogendoorn, P.C.W., and Snaar-Jagalska, B.E.
- Subjects
drug synergism ,p53 ,anti-cancer drug screen ,molecular targeted therapy ,tumour growth ,zebrafish ,Ewing sarcoma - Published
- 2014
17. UM Cure 2020 - A consortium of European experts in uveal melanoma to identify new therapies for patients with metastatic disease
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Coupland, S., primary, Kalirai, H., additional, Jager, M., additional, Jochemsen, A.G., additional, van der Velden, P.A., additional, Snaar-Jagalska, B.E., additional, Dhomen, N., additional, Marais, R., additional, Romanowska Dixon, B., additional, Elas, M., additional, Mione, M.C., additional, Valente, A., additional, Ryll, B., additional, Ruijtenbeek, R., additional, Prestat, A., additional, Hafsi, H., additional, Barnhill, R., additional, Cassoux, N., additional, Decaudin, D., additional, Lantz, O., additional, Piperno-Neumann, S., additional, Stern, M.H., additional, and Roman-Roman, S., additional
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- 2016
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18. Innovative approaches to establish and characterize primary cultures: an ex vivo 3D system and the zebrafish model
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Liverani, C., primary, La Manna, F., additional, Groenewoud, A., additional, Mercatali, L., additional, Van Der Pluijm, G., additional, Pieri, F., additional, Cavaliere, D., additional, Alessandro, D.V., additional, Spadazzi, C., additional, Miserocchi, G., additional, Bongiovanni, A., additional, Recine, F., additional, Riva, N., additional, Amadori, D., additional, Tasciotti, E., additional, Marcantognini, G., additional, Fausti, V., additional, Snaar-Jagalska, B.E., additional, and Ibrahim, T., additional
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- 2016
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19. CXCL14, CXCR7 expression and CXCR4 splice variant ratio associate with survival and metastases in Ewing sarcoma patients
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Sand, L.G.L., primary, Scotlandi, K., additional, Berghuis, D., additional, Snaar-Jagalska, B.E., additional, Picci, P., additional, Schmidt, T., additional, Szuhai, K., additional, and Hogendoorn, P.C.W., additional
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- 2015
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20. miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression
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Zoni, E., primary, van der Horst, G., additional, van de Merbel, A.F., additional, Chen, L., additional, Rane, J.K., additional, Pelger, R.C.M., additional, Collins, A.T., additional, Visakorpi, T., additional, Snaar-Jagalska, B.E., additional, Maitland, N.J., additional, and van der Pluijm, G., additional
- Published
- 2015
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21. beta1 integrin inhibition elicits a prometastatic switch through the TGFbeta-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer
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Truong, H.H., Xiong, J., Ghotra, V.P., Nirmala, E., Haazen, L., Devedec, S.E. Le, Balcioglu, H.E., He, S., Snaar-Jagalska, B.E., Vreugdenhil, E., Meerman, J.H., Water, B. Van de, Danen, E.H.J., Truong, H.H., Xiong, J., Ghotra, V.P., Nirmala, E., Haazen, L., Devedec, S.E. Le, Balcioglu, H.E., He, S., Snaar-Jagalska, B.E., Vreugdenhil, E., Meerman, J.H., Water, B. Van de, and Danen, E.H.J.
- Abstract
Item does not contain fulltext, Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the beta1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of beta1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked beta1 integrin function or knockdown of beta1 switched the migratory behavior of human and mouse E-cadherin-positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor-beta (TGFbeta) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box-binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFbeta receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in beta1 integrin-deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that beta1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting beta1 integrins may have undesirable effects in TNBC.
- Published
- 2014
22. Robotic injection of zebrafish embryos for high-throughput screening in disease models
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Spaink, H.P., Cui, C., Wiweger, M.I., Jansen, H.J., Veneman, W.J., Marin-Juez, R., Sonneville, J. de, Ordas, A., Torraca, V., Ent, W. van der, Leenders, W.P.J., Meijer, A.H., Snaar-Jagalska, B.E., Dirks, R.P., Spaink, H.P., Cui, C., Wiweger, M.I., Jansen, H.J., Veneman, W.J., Marin-Juez, R., Sonneville, J. de, Ordas, A., Torraca, V., Ent, W. van der, Leenders, W.P.J., Meijer, A.H., Snaar-Jagalska, B.E., and Dirks, R.P.
- Abstract
Item does not contain fulltext, The increasing use of zebrafish larvae for biomedical research applications is resulting in versatile models for a variety of human diseases. These models exploit the optical transparency of zebrafish larvae and the availability of a large genetic tool box. Here we present detailed protocols for the robotic injection of zebrafish embryos at very high accuracy with a speed of up to 2000 embryos per hour. These protocols are benchmarked for several applications: (1) the injection of DNA for obtaining transgenic animals, (2) the injection of antisense morpholinos that can be used for gene knock-down, (3) the injection of microbes for studying infectious disease, and (4) the injection of human cancer cells as a model for tumor progression. We show examples of how the injected embryos can be screened at high-throughput level using fluorescence analysis. Our methods open up new avenues for the use of zebrafish larvae for large compound screens in the search for new medicines.
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- 2013
23. Single-molecule imaging technique to study the dynamic regulation of GPCR function at the plasma membrane
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Snaar-Jagalska, B.E., Cambi, A., Schmidt, T., Keijzer, S. de, Snaar-Jagalska, B.E., Cambi, A., Schmidt, T., and Keijzer, S. de
- Abstract
Item does not contain fulltext, The lateral diffusion of a G-protein-coupled receptor (GPCR) in the plasma membrane determines its interaction capabilities with downstream signaling molecules and critically modulates its function. Mechanisms that control GPCR mobility, like compartmentalization, enable a cell to fine-tune its response through local changes in the rate, duration, and extent of signaling. These processes are known to be highly dynamic and tightly regulated in time and space, usually not completely synchronized in time. Therefore, bulk studies such as protein biochemistry or conventional confocal microscopy will only yield information on the average properties of the interactions and are compromised by poor time resolution. Single-particle tracking (SPT) in living cells is a key approach to directly monitor the function of a GPCR within its natural environment and to obtain unprecedented detailed information about receptor mobility, binding kinetics, aggregation states, and domain formation. This review provides a detailed description on how to perform single GPCR tracking experiments.
- Published
- 2013
24. Lysophosphatidic acid- and Gß-dependent activation of Dictyostelium MAP kinase ERK2
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Schenk, P.W., Epskamp, S.J.P., Knetsch, M.L.W., Harten, V., Lagendijk, E.L., Duijn, B. van, Snaar-Jagalska, B.E., and TNO Voeding
- Subjects
Nutrition - Published
- 2001
25. Quantification of GPCR internalization by single-molecule microscopy in living cells.
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Serge, A., Keijzer, S. de, Hemert, F. Van, Hickman, M.R., Hereld, D., Spaink, H.P., Schmidt, T., Snaar-Jagalska, B.E., Serge, A., Keijzer, S. de, Hemert, F. Van, Hickman, M.R., Hereld, D., Spaink, H.P., Schmidt, T., and Snaar-Jagalska, B.E.
- Abstract
1 juni 2011, Item does not contain fulltext, Receptor internalization upon ligand stimulation is a key component of a cell's response and allows a cell to correctly sense its environment. Novel fluorescent methods have enabled the direct visualization of the agonist-stimulated G-protein-coupled receptors (GPCR) trafficking in living cells. However, it is difficult to observe internalization of GPCRs in vivo due to intrinsic autofluorescence and cytosolic signals of fluorescently labeled GPCRs. This study uses the superior positional accuracy of single-molecule fluorescence microscopy to visualize in real time the internalization of Dictyostelium discoideum cAMP receptors, cAR1, genetically encoded with eYFP. This technique made it possible to follow the number of receptors in time revealing that the fraction of cytosolic receptors increases after persistent agonist stimulation and that the majority of the receptors were degraded after internalization. The observed internalization process was phosphorylation dependent, as shown with the use of a phosphorylation deficient cAR1 mutant, cm1234-eYFP, or stimulation with an antagonist, Rp-cAMPS that does not induce receptor phosphorylation. Furthermore, experiments done in mound-stage cells suggest that intrinsic, phosphorylation-induced internalization of cAR1 is necessary for Dictyostelium wild type cells to progress properly through multicellular development. To our knowledge, this observation illustrates for the first time phosphorylation-dependent internalization of single cAR1 molecules in living cells and its involvement in multicellular development. This very sensitive imaging of receptor internalization can be a useful and universal approach for pharmacological characterization of GPCRs in other cell types.
- Published
- 2011
26. S35 - Innovative approaches to establish and characterize primary cultures: an ex vivo 3D system and the zebrafish model
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Liverani, C., La Manna, F., Groenewoud, A., Mercatali, L., Van Der Pluijm, G., Pieri, F., Cavaliere, D., Alessandro, D.V., Spadazzi, C., Miserocchi, G., Bongiovanni, A., Recine, F., Riva, N., Amadori, D., Tasciotti, E., Marcantognini, G., Fausti, V., Snaar-Jagalska, B.E., and Ibrahim, T.
- Published
- 2016
- Full Text
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27. Distinct functions for ERK1 and ERK2 in cell migration processes during zebrafish gastrulation.
- Author
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Krens, S.F.G., He, S., Lamers, G.E.M., Meijer, A.H., Bakkers, J., Schmidt, T., Spaink, H.P., Snaar-Jagalska, B.E., Krens, S.F.G., He, S., Lamers, G.E.M., Meijer, A.H., Bakkers, J., Schmidt, T., Spaink, H.P., and Snaar-Jagalska, B.E.
- Abstract
The MAPKs are key regulatory signaling molecules in many cellular processes. Here we define differential functions for ERK1 and ERK2 MAPKs in zebrafish embryogenesis. Morpholino knockdown of ERK1 and ERK2 resulted in cell migration defects during gastrulation, which could be rescued by co-injection of the corresponding mRNA. Strikingly, Erk2 mRNA cross-rescued ERK1 knockdown, but erk1 mRNA was unable to compensate for ERK2 knockdown. Cell-tracing experiments revealed a convergence defect for ERK1 morphants without a severe posterior-extension defect, whereas ERK2 morphants showed a more severe reduction in anterior-posterior extension. These defects were primary changes in gastrulation cell movements and not caused by altered cell fate specification. Saturating knockdown conditions showed that the absence of FGF-mediated dual-phosphorylated ERK2 from the blastula margin blocked initiation of epiboly, actin and tubulin cytoskeleton reorganization processes and further arrested embryogenesis, whereas ERK1 knockdown had only a mild effect on epiboly progression. Together, our data define distinct roles for ERK1 and ERK2 in developmental cell migration processes during zebrafish embryogenesis., The MAPKs are key regulatory signaling molecules in many cellular processes. Here we define differential functions for ERK1 and ERK2 MAPKs in zebrafish embryogenesis. Morpholino knockdown of ERK1 and ERK2 resulted in cell migration defects during gastrulation, which could be rescued by co-injection of the corresponding mRNA. Strikingly, Erk2 mRNA cross-rescued ERK1 knockdown, but erk1 mRNA was unable to compensate for ERK2 knockdown. Cell-tracing experiments revealed a convergence defect for ERK1 morphants without a severe posterior-extension defect, whereas ERK2 morphants showed a more severe reduction in anterior-posterior extension. These defects were primary changes in gastrulation cell movements and not caused by altered cell fate specification. Saturating knockdown conditions showed that the absence of FGF-mediated dual-phosphorylated ERK2 from the blastula margin blocked initiation of epiboly, actin and tubulin cytoskeleton reorganization processes and further arrested embryogenesis, whereas ERK1 knockdown had only a mild effect on epiboly progression. Together, our data define distinct roles for ERK1 and ERK2 in developmental cell migration processes during zebrafish embryogenesis.
- Published
- 2008
28. Abberant chemotaxis and differentiation in Dictyostelium mutant fgdC with a defective regulation of receptor-stimulated phosphoinositidase C
- Author
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Bominaar, A.A., Kesbeke, F., Snaar-Jagalska, B.E., Peters, D.J., Schaap, P., and Haastert, P.J. van
- Abstract
Dictyostelium cells use extracellular cyclic AMP both as a chemoattractant and as a morphogen inducing cell-type-specific gene expression. Cyclic AMP binds to surface receptors, activates one or more G-proteins, and stimulates adenylate cyclase, guanylate cyclase and phosphoinositidase C. Mutant fgdC showed aberrant chemotaxis, and was devoid of cyclic AMP-induced gene expression and differentiation. Both the receptor- and G-protein-mediated stimulation of adenylate cyclase and guanylate cyclase were unaltered in mutant fgdC as compared to wild-type cells. In wild-type cells phosphoinositidase C was activated about twofold by the cyclic AMP receptor. In mutant fgdC cells, however, the enzyme was inhibited by about 60%. These results suggest that phosphoinositidase C is regulated by a receptor-operated activation/inhibition switch that is defective in mutant fgdC. We conclude that activation of phosphoinositidase C is essential for Dictyostelium development.
- Published
- 1991
29. Chemotaxis to cyclic AMP and folic acid is mediated by different G proteins in Dictyostelium discoideum
- Author
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Kesbeke, F., Haastert, P.J.M. van, Wit, R.J.W. de, and Snaar-Jagalska, B.E.
- Published
- 1990
30. Abberant chemotaxis and differentiation in Dictyostelium mutant fgdC with a defective regulation of receptor-stimulated phosphoinositidase C
- Author
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Bominaar, A.A., primary, Kesbeke, F., additional, Snaar-Jagalska, B.E., additional, Peters, D.J., additional, Schaap, P., additional, and Van Haastert, P.J., additional
- Published
- 1991
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31. Signal transduction in Dictyostelium fgd A mutants with a defective interaction between surface cAMP receptors and a GTP-binding regulatory protein
- Author
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Kesbeke, F., Snaar-Jagalska, B.E., and Haastert, P.J. van
- Abstract
Transmembrane signal transduction was investigated in four Dictyostelium discoideum mutants that belong to the fgd A complementation group. The results show the following. (a) Cell surface cAMP receptors are present in fgd A mutants, but cAMP does not induce any of the intracellular responses, including the activation of adenylate or guanylate cyclase and chemotaxis. (b) cAMP induces down-regulation and the covalent modification (presumably phosphorylation) of the cAMP receptor. (c) The inhibitory effects of GTP gamma S and GDP beta S on cAMP binding are reduced; the stimulatory effect of cAMP on GTP gamma S binding is lost in fgd A mutants. (d) Basal high-affinity GTPase activity is reduced 40% and the stimulatory effect of cAMP is decreased from 40% in wild type to 30% in fgd A. (e) GTP-mediated stimulation and inhibition of adenylate cyclase is normal in mutant membranes. The results suggest a defective interaction between cell surface cAMP receptors and a specific G-protein in fgd A mutants. This interaction appears to be essential for nearly all signal transduction pathways in Dictyostelium discoideum.
- Published
- 1988
32. Dictyostelium discoideum mutant synag 7 with altered G-protein-adenylate cyclase interaction
- Author
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Snaar-Jagalska, B.E., primary and Van Haastert, P.J., additional
- Published
- 1988
- Full Text
- View/download PDF
33. THE DEVELOPMENT OF ELISA TO DETERMINE ABSCISIC ACID AND INDOLE-3-ACETIC ACID IN BULBOUS CROPS
- Author
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Franssen, J.M., primary, Snaar-Jagalska, B.E., additional, and van der Hulst, C.Th.C., additional
- Published
- 1986
- Full Text
- View/download PDF
34. Ginsenosides as selective glucocorticoid drugs
- Author
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Halima, M., Meijer, A.H., Schaaf, M.J.M., Wang, M., Wezel, G.P. van, Snaar-Jagalska, B.E., Martin, N.I., Meijer, O.C., Dalla Valle, L., and Leiden University
- Subjects
Ginsenosides ,Neutrophils ,Agonist ,Antagonist ,Glucocorticoid receptor ,Anti-inflammatory ,Prodrug ,Side effects ,Transrepression activity ,Transactivation activity - Abstract
Glucocorticoids are potent anti-inflammatory drugs widely used clinically to treat various inflammatory and immune conditions. However, two main clinical problems limit their use. GCs trigger severe side effects and they induce acquired glucocorticoid resistance, especially during chronic systemic treatment [6-11]. Therefore, developing novel strategies to improve the treatment inflammatory and immune conditions becomes urgent. Here, we present evidence that ginsenosides act as selective GR agonists, antagonists, and prodrugs. Moreover, our data illustrate that the number and positions of glucose groups bound to the steroid backbone of ginsenosides and different chemical structures are essential factors underlying the differential mechanistic effects of ginsenosides. Understanding the molecular mechanisms and the effects of natural compound (ginsenosides) opens a novel road towards developing improved anti-inflammatory GCs. Attaching one glucose group to classical GCs produced selective Gr agonists, such as GDex and GPdn, which exert anti-inflammatory effects without triggering side effects due to the absence of GR transactivation activities. Attaching two glucose groups to classical GCs resulted in the creation of GC prodrugs, such as GbPdn, which mediates its action locally at the site of inflammation, dependent on GBA2 activity, without triggering side effects.
- Published
- 2023
35. Forces and symmetries in cells and tissues
- Author
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Eckert, J., Schmidt, T., Gloerich, M., Ladoux, B., Aarts, J., Noort, S.J.T. van, Snaar-Jagalska, B.E., and Leiden University
- Subjects
Cells and Tissues ,Mechanobiology ,Cell-cell adhesion ,Tissue symmetry ,Cell mechanics ,Traction forces - Abstract
The way organisms develop from the initial single-cellular state to a complex final assembly like the human body, and how the final body is maintained throughout life, is one of the greatest mysteries and it’s understanding one of the biggest scientific challenges. Lately, it came as a surprise that the initial assembly and the later maintenance of integrity is not only determined by intricate biochemical communication networks, but in part by physical forces that cells, their neighbors, and their environment apply in a bidirectional manner. The resulting collectivity of cell behavior determines the development of organisms, and are crucial to the health and disease state of the organism.In this thesis, we developed and utilized concepts from physics to quantitatively understand forces that develop between cells and their environment, and towards neighboring cells, and how the interplay between these forces regulates the arrangement, shape, and topology of tissue. The topics range from the development of novel experimental methods to the combination of experimental observations with theoretical descriptions. Our results contribute to a better understanding of cell and tissue integrity.
- Published
- 2022
36. Modelling metastatic melanoma in zebrafish
- Author
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Groenewoud, A., Snaar-Jagalska, B.E., Jochemsen, A.G., Wezel, G.P. van, Spaink, H.P., Le Dévédec, S.E., Dijke, P. ten, Engel, F.B., and Leiden University
- Subjects
Xenograft ,Melanin ,sense organs ,Melanoma ,Zebrafish ,Cancer - Abstract
Death in all types of melanomas is generally caused by metastasis. Uveal melanoma (UM) is the most common intraocular melanoma, there are currently no (patient-derived) animal models that faithfully recapitulate metastatic dissemination of UM. Here we generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma. In doing so we can recapitulate the etiology of cancer in its totality. Subsequently, we developed a patient-derived zebrafish xenograft (zf-PDX) model, using spheroid cultures generated from metastatic and primary UM tissues. Harnessing this versatile model, we reveal high sensitivity of circulating UM cells to ferroptosis induction in vivo by Erastin and RSL3, implicating ferroptosis as a new potential therapy in metastatic UM.Increased melanin levels in cutaneous melanoma are associated with decreased patient survival. Melanin levels in primary uveal melanoma patient cells positively correlate with their metastatic potential in zebrafish. Modulation of melanin levels of pan-melanoma cells results in enhanced/reduced metastatic potential upon increased or decreased melanin levels, respectively. Melanin depletion sensitizes melanoma cells to ferroptosis inducers in zebrafish leading to a decreased metastatic burden. Collectively, our data identify melanin biosynthetic enzymes as potential future target to treat melanoma and show that melanin protects metastasizing melanoma cells from ferroptosis.
- Published
- 2022
37. Boosting the host immune system to fight tuberculosis
- Author
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Boland, R., Meijer, A.H., Spaink, H.P., Vaart, M. van der, Wezel, G.P. van, Snaar-Jagalska, B.E., Barz, M., Ottenhoff, T.H.M., Houben, E.N.G., and Leiden University
- Subjects
Host-directed Therapeutics ,Tamoxifen ,Autophagy ,Amiodarone ,Tuberculosis ,Lysosomal pathway ,Zebrafish ,Mycobacterium - Abstract
New drugs for use as tuberculosis (TB) treatment are needed due to the constrains of classical antibiotics against TB and the rise of antibiotic-resistant strains, making TB a harder and harder disease to treat. This thesis is focused on using the in vivo whole animalzebrafish embryo model for TB to evaluate potential anti-TB host-directed therapeutics (HDTs) arising from in vitro screens. Although in vitro screens for HDTs using cellular models can be performed at high throughput, a limiting step is the validation in whole animal models and translation of results to clinical applications. Due to the complex infection dynamics of mycobacteria, the use of whole animal models is indispensable in research into TB and the zebrafish model has contributed key findings about host-pathogen dynamics during mycobacterial infection. One of the most promising host targets of HDTs is autophagy, which is recognized as an important host-protective pathway. Boosting autophagy levels using HDTs could be a way to overcome the pathogen’s autophagy evasion strategies and could therefore be a promising therapeutic route. For this thesis we took advantage of the possibilities of the zebrafish embryo model for TB and the zebrafish toolkit to study several autophagy-modulating HDTs as potential anti-TB drugs.
- Published
- 2022
38. The Function of Toll-like receptor 2 in Infection and Inflammation
- Author
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Hu, W., Spaink, H.P., Verbeek, F.J., Wezel, G.P. van, Snaar-Jagalska, B.E., Merks, R.M.H., Ottenhoff, T.H.M., Bitter, W., and Leiden University
- Subjects
Tail wounding ,Cell tracking ,TLR2 ,zebrafish larvae ,Mycobacterium tuberculosis ,leukocyte biology ,Nontuberculous mycobacteria - Abstract
The function of TLRs in innate immunity has aroused worldwide attention soon after its discovery. Because of the broad functions of TLR2 in innate immunity, the drive for the development of TLR2-targeted vaccines or therapeutic treatments has accelerated in the last decades. However, its dual role in both activation and suppression of innate immune responses makes it very difficult to use the available results from basic research for the development of clinical trials. In addition, it is still not clear what is the function of TLR2 in regulating phagocytic cell migration. Therefore, we aimed to determine the function of TLR2 in mycobacterial infection and explore its role in regulating phagocytic cell migration in inflammatory tissue by using a zebrafish larval model in this thesis. We showed that infection of a tlr2 mutant in zebrafish larvae leads to a higher mycobacterial burden, accompanied by a lower number of granulomas and increased extracellular bacterial growth. Through a tail fin wounding and tail fin infection zebrafish model, we demonstrated that tlr2 is involved in modulating leukocyte migration. This thesis provides a better understanding of the functions of TLR2 in innate immune responses to infection and tissue wounding.
- Published
- 2021
39. Tailoring the tools to study prostate cancer metastasis
- Author
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La Manna, F., Pelger, R.C.M., Kruithof-de Julio, M., Cohen, A., Osanto, S., Snaar-Jagalska, B.E., Danen, E.H.J., Kloen, P., and Leiden University
- Subjects
Organoids ,Prostate cancer ,Drug screening ,Bibliometric analysis ,Patient-derived xenograft ,Bone metastasis - Abstract
The work included in this thesis is aimed at developing novel tools to advance our understanding of prostate cancer. The clinical problem of prostate cancer is presented and discussed in the wider context of the current clinical knowledge, highlighting the genetic mechanisms at its base. A dedicated chapter focuses on bone metastases, highly morbid feature of advanced prostate cancer, discussing the known mechanisms and the available models to study it in translational research. Then, moving from the molecular analysis of clinical specimens of bone metastasis, a biochemical pathway is identified and further studied in vitro, ex vivo and in vivo, validating the initial findings. A novel, early-stage prostate cancer patient-derived xenograft is presented and extensively characterized and implemented in a drug screening. This allowed to screen the effect of over 70 known drugs on prostate cancer models, using three-dimensional cultures and a semi-automated platform. As all research builds on previously established findings, a bibliometric analysis tool is presented, to assist in the generation of a knowledge network arranged by topic and impact of research. All these aspects and findings are then discussed in the context of the current direction of prostate cancer research, its emerging tools and its long-known challenges.
- Published
- 2021
40. Towards treatment of liver fibrosis: Cells, targets and models
- Author
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Helm, D. van der, Verspaget, H.W., Hoek, B. van, Coenraad, M.J., Hiemstra, P.S., Alwayn, I.P.J., Snaar-Jagalska, B.E., Reinders, M.E.J., Hoogduin, M.J., and Leiden University
- Subjects
CCL4 ,Cirrhosis ,Hepatology ,Liver ,Thoracic aortic aneurysm (TAA) ,Hepatocellular carcinoma (HCC) ,Fibrosis ,Mesenchymal stromal cell (MSC) ,Zebrafish - Abstract
This thesis describes the possible applicability of mesenchymal stromal cells (MSCs) in the treatment of liver fibrosis. In CCL4 induced animal models for liver fibrosis, we showed that local administration of MSCs after partial hepatectomy, results in a dose‐dependent on‐site amelioration of fibrosis. Furthermore, we compared the pro-regenerative and anti-fibrotic effects of four different subpopulations of MSCs, categorized on Endoglin (CD105) and VCAM (CD106) membrane expression. Our results showed that VCAM-positive subpopulations of MSCs are superior compared to VCAM-negative subpopulations in relation to their anti-fibrotic and pro-regenerative properties. In another study we showed that TAA induce liver fibrogenesis in zebrafish embryos through mechanisms similar to man and mice. In addition, we found that MSCs ameliorate fibrogenesis in this model.CRIPTO-1 is an (onco)foetal protein and is correlated to poor prognosis in HCC. The observations of our HCC study are suggestive for the existence of a more aggressive subgroup of HCCs recognized by their high CRIPTO-1 expression which also seems to be resistant to Sorafenib treatment. Cell survival and cell proliferation are some of the processes stimulated by CRIPTO-1, which are also known to be important during liver regeneration and fibrogenesis. We identified that multiple species show enhanced CRIPTO-1 during fibrogenesis and that elevated CRIPTO-1 plasma levels in humans with cirrhosis normalize after liver transplantation.
- Published
- 2021
41. Group benefits from genomic instability: A tale of antibiotic warriors in Streptomyces
- Author
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Zhang, Z., Rozen, D.E., Claessen, D., Wezel, G.P. van, Klinkhamer, P.G.L., Snaar-Jagalska, B.E., Riebel, K., Aanen, D.K., Hoskisson, P., and Leiden University
- Subjects
Genomic instability ,Cooperation ,Microbial evolution ,Division of labor ,Genomic rearrangements ,Multicellularity ,Antibiotic production ,Kin selection - Abstract
Streptomyces are filamentous bacteria that produce more than two-thirds of known antibiotics. Due to their multicellular lifestyle as well as their prolific production of secondary metabolites, Streptomyces are of unique fundamental and applied importance. However, Streptomyces have unstable genomes, an attribute that can cause genomic rearrangements and dramatically alter their phenotype. Previous studies have failed to explain this phenomenon. In this dissertation, we investigate the evolutionary functions and mechanisms of genomic instability in Streptomyces coelicolor. We first find that a subpopulation of cells generated through large genomic rearrangements becomes specialized to produce antibiotics. This results in a division of labor which benefits the entire colony, while the yield and diversity of antibiotics are maximized, despite significant fitness costs to this altruistic subpopulation. Next, we show that these altruistic mutants continue to lose fitness due to the irreversible accumulation of large deletions and deleterious mutations, coupled to an increased mutation rate. Finally, we explore the molecular consequences of large genomic rearrangements for development and antibiotic production using detailed proteomics and metabolomics analyses, which highlight key pathways that are impacted by these genomic events. Overall, this dissertation provides new insights of genomic instability in Streptomyces.
- Published
- 2020
42. Zebrafish xenograft model: Identification of novel mechanisms driving prostate cancer metastasis
- Author
-
Chen, L., Snaar-Jagalska, B.E., Kruithof-de Julio, M., Wezel, G.P. van, Meijer, A.H., Raaijmakers, M.H.G.P., Dijke, P. ten, Thalmann, G.N., and Leiden University
- Subjects
Prostate cancer ,Microenvironment ,Mechanotransduction ,Cancer stem cells ,NGS ,Zebrafish ,Metastasis - Abstract
Prostate cancer (PCa) is one of the most prevalent cancer in males. Although the majority of the patients can benefit from the present clinical treatments, 20%-30% of the patients who originally respond to the therapy still develop incurable, castration-resistance bone metastases, which is a main cause of death in PCa . In this thesis, I combined an advanced zebrafish xenograft model with in vitro cellular approaches and mice xenografts to study the early stage of PCa metastasis. Using this comprehensive esearch platform, I identified multiple key signaling pathways that play essential roles in promoting the onset of PCa metastatis. The pathways I discovered include Cripto-associated EMT plasticity, CDC-42-N-Wasp-Cortactin associated mechanosensing and mechanotransduction, microenvironment dependent NF-ĸB-Activin A signaling pathway, and AMPK-Autophagy dependent metabolic stress coping pathway.
- Published
- 2020
43. Development of novel anti-cancer strategies utilizing the zebrafish xenograft model
- Author
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Chen, Q., Snaar-Jagalska B.E., Bonnet S.A., Wezel, G.P. van, Meijer, A.H., Kros, A., Dijke, P. ten, Jager, M., and Leiden University
- Subjects
Liposome ,Anti-cancer ,Macrophage ,Angiogenesis ,Photoactivated chemotherapy ,Zebrafish ,Photodynamic therapy - Abstract
In this thesis, we will utilize embryonic zebrafish tumour models to understand the interaction between engrafted human cancer cells and macrophages from the host, test drug administration modalities and anti-cancer efficacies of newly-developed PDT and PACT compounds, and test a light-triggered liposomal system for targeted drug delivery specifically to cancer cells in vivo. In chapter 2, we investigate the role of macrophages in tumour-induced angiogenesis. We show that macrophage-dependent angiogenesis is driven by macrophage recruitment to lactic acid secreted by glycolytic B16 melanoma cells. Chemical inhibition of macrophages and glycolysis blocks the initiation of angiogenesis in these models, suggesting that macrophages attracted to glycolytic melanoma cells contribute to the tumour-induced angiogenesis process.In chapters 3 and 4, we explore novel PDT and PACT compounds, respectively, for treatment of conjunctival melanoma in zebrafish. We inject conjunctival melanoma cells into the retro-orbital site to establish an orthotopic model and into the Duct of Cuvier to generate an ectopic model. Our results prove that zebrafish provides a fast vertebrate cancer model to test the optimal administration regimen of drugs, conditions of light irradiation, host toxicity and anti-cancer efficacy of PDT and PACT drugs against conjunctival melanoma.In chapter 5, we focus on modifying liposomes to be light triggered in order to deliver drugs specifically to cancer cells. We inject MDA231 breast cancer cells into the Duct of Cuvier at 2 days post fertilization (dpf) to initiate metastasis to the CHT. We successfully demonstrate that light-triggered, cell-specific delivery of liposome-encapsulated doxorubicin reduces the xenograft cancer cell burden without enhanced cytotoxicity of the zebrafish embryos. In chapter 6, we summarize the novel anti-cancer strategies, which we have developed using zebrafish xenograft models. In the same chapter, we frame our findings in the current scientific landscape and discuss future perspectives.
- Published
- 2020
44. RNA splicing in breast cancer progression
- Author
-
Koedoot, E., Water, B. van de, Le Dévédect, S.E., Irth, H., Bouwstra, J.A., Martens, J.W.M., Sonnenberg, A., Dijke, P. ten, Snaar-Jagalska, B.E., and Leiden University
- Subjects
Breast cancer ,RNA splicing ,siRNA screening ,Transcriptomics - Abstract
In this thesis, we aimed to better understand the underlying mechanisms involved in TNBC progression and metastasis formation and discover new targets to reduce breast cancer related deaths. We performed an imaging-based RNAi phenotypic cell migration screen in two highly motile TNBC cancer cell lines to provide a repository of signaling determinants that functionally drive TNBC cell motility. Interestingly, two modulators essential for cancer cell migration were known to be involved in RNA splicing, making us decide to focus on the role of RNA splicing in breast cancer progression. We next summarized the current knowledge about splicing factors in breast cancer development and progression and identified co-regulated splicing factors that were associated with aggressive breast cancer phenotypes and metastasis formation that was not only restricted to breast cancer, increasing the global understanding of the role of the spliceosome in cancer development and progression. Moreover, the role of splicing factors in two major processes in cancer progression, cell migration and proliferation, was examined. Finally, using RNA sequencing, we systematically compared the transcriptomes of 14 breast cancer cell lines cultured both in 2D and 3D conditions to unravel the reprogramming that is associated with the invasive phenotype of basal B TNBC.
- Published
- 2019
45. Selective autophagy in host defense against mycobacterial infection
- Author
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Zhang, R., Meijer, A.H., Vaart, M. van der, Varela, M., Spaink, H.P., Snaar-Jagalska, B.E., Ottenhoff, T.H.M., Elks, P.M., and Leiden University
- Subjects
Macrophage ,p62 ,Autophagy ,Mycobacterium marinum ,Lc3 ,Tuberculosis ,Zebrafish ,Dram1 ,Optineurin - Abstract
The effective treatment of tuberculosis (TB) remains a major challenge to global health. Drug-resistant Mycobacterium tuberculosis (Mtb) strains and co-infection with HIV further increase the difficulty of controlling TB. Thus, under the current situation, it is essential to develop effective treatment strategies for Mtb infections. Autophagy is a lysosomal degradation process and substantial experimental evidence has demonstrated that autophagy is an important host immune defense mechanism against mycobacterial infection. However, the development of effective therapies requires a better understanding of the interaction between the host and invading pathogens to identify host processes that can be targeted. A useful tool for such studies is the zebrafish model for TB. Zebrafish can be infected with Mycobacterium marinum (Mm), which is closely related to Mtb and causes similar disease characteristics. Taking advantage of the zebrafish TB model, this thesis presents new in vivo evidence for the important function of autophagy to inhibit mycobacterial proliferation inside macrophages. Furthermore, this study supports that stimulating the innate host defense processes that are dependent on the autophagy modulator, Dram1, and the selective autophagy receptors, p62 and Optineurin, could be a useful strategy to explore for adjunctive treatment of antibiotic-resistant TB infections.
- Published
- 2018
46. Novel functions of MDMX and innovative therapeutic strategies for melanoma
- Author
-
Heijkants, R.C., Dijke, P. ten, Jochemsen, A.G., Jager, M.J., Burgering, B.M.T., Snaar-Jagalska, B.E., Doorn, R. van, and Leiden University
- Subjects
p53 ,Molecular cell biology ,Uveal melanoma ,Synergism ,Melanoma ,MDMX - Abstract
The focus of this thesis is uveal melanoma (UM) which, once metastasized, is lethal due to lack of effective treatment options. To repress p53 activity approximately 65% of UM tumors express high levels of the p53 inhibitory proteins MDMX or MDM2. The aim of this thesis is to unravel the oncogenic function of MDMX and provide new treatment options for patients with metastasized UM. Chapter 2 describes the regulation of the transcriptome by MDMX in UM and proposes novel p53-independent effects of MDMX, i.e. FOXO inhibition. In chapter 3 the opportunities of a combined targeting of two common signaling pathways as therapeutic intervention for metastasized UM patients is investigated. Genetic interference with either MDMX or PKC δ expression or activity showed that beneficial effects can already be achieved by a more specific targeting, which is presumable less toxic to the patient. In chapter 4 it is described, opposed to what has been reported before, that enhancer of zeste homolog 2 (EZH2) inhibition poses a valuable novel therapeutic invention for UM. In chapter 5 it is shown that combining two clinically approved drugs, Quisinostat and Flavopiridol, could serve as an effective therapeutic intervention for UM patients.
- Published
- 2018
47. A time-space translation mechanism for patterning the vertebrate anteroposterior axis
- Author
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Zhu, K., Durston, A.J., Spaink, H.P., Stern, C.D., Mummery, C.L., Wezel, G.P. van, Snaar-Jagalska, B.E., and Leiden University
- Subjects
Hox genes ,animal structures ,Time space translation ,Xenopus ,embryonic structures ,Anteroposterior patterning ,Hox interactions - Abstract
My PhD project studies how the temporally sequential Hox gene expression is regulated during head-tail patterning of the frog embryo. This question has not been solved and remains one of the greatest unsolved mysteries in developmental biology. Currently, a very attractive explanation attributes sequential Hox gene activation to progressive opening of the chromosome, because it parallels the linear arrangement of Hox genes on the chromosome. While promising, this explanation is surrounded by extra complexities that ensure Hox expression is synchronized between different cells. By using gain-of-function and loss-of-function approaches, I discovered that Hox-Hox interactions play a crucial role in the regulation of Hox expression, and for the first time, I dissected different roles for these interactions in axis formation. The findings are likely to resolve the above complexities, and reveal a new facet of the mechanisms underlying Hox gene regulation. Furthermore, by timed modulation of the actions of BMP signaling, I showed that there is a BMP-dependent timing mechanism in the head that could be continued by the Hox temporal sequence in the trunk. The two constitute an integrative timer which can be translated into spatial patterns of gene expression along the whole head-tail axis via a BMP/anti-BMP dependent mechanism.
- Published
- 2017
48. Cell-autonomous and host-dependent CXCR4 signaling in cancer metastasis : insights from a zebrafish xenograft model
- Author
-
Tulotta, C., Meijer, A.H., Snaar-Jagalska, B.E., Spaink, H.P., Hertog, J. den, Jager, M., Feng, Y., and Leiden University
- Subjects
CXCR4 ,Immune system ,Tumor microenvironment ,Cancer metastasis ,CXCL12 ,Zebrafish xenograft - Abstract
Metastatic cancer is aggressive and rapidly developing, making it difficult to treat, often leading to mortality. Cancer cells are not isolated, but rather survive and proliferate in complex tumor microenvironments. Importantly, tumor cells “educate” immune cells to play a supportive role during cancer progression. Therefore, understanding how cancer cells and immune cells communicate is of pivotal importance to limit tumor progression. In this project, we identified the chemokine receptor CXCR4 and its correspondent ligand, CXCL12, as a key couple that regulate the interaction between tumor cells and immune cells. The research has been performed using the zebrafish xenograft model. This model offers the advantage of looking at tumor-immune cell interaction on a single cell level and in a living whole organism. The transparency of the embryo and the current genetic tools available, in combination with the ease in pharmacological approaches, make this model an excellent tool to determine and impair cancer-microenvironment inter-communication. We showed that inhibiting the CXCL12-CXCR4 axis either on the tumor side or on the immune cell side leads to impaired tumor progression, during the early phases of metastasis formation. We propose that blocking cancer-stroma communication represents a promising therapeutic strategy to fight cancer.
- Published
- 2016
49. Mechanisms of Ewing sarcoma metastasis : biochemistry and biophysics
- Author
-
Beletkaia, E., Schmidt, T., Snaar-Jagalska, B.E., Fenz, S.F., Bünemann, M., Dogterom, M., Eliel, E., Hogendorn, P.C.W., and Leiden University
- Subjects
Mechanisensing ,CXCR4 ,GPCR ,Single-molecule ,Ewing sarcoma ,Metastasis - Abstract
Ewing sarcoma (ES) is a special type of bone cancer, first described by Dr. James Ewing in his paper __Diffusive endothelioma of bone__. Today Ewing sarcoma represents the second most common bone cancer among adolescents and young adults. Contrary to the positive achievement in treatment of localized tumors, the long-term (5-years) survival for Ewing sarcoma patients with metastasis, however, remain below the 30% mark. In this thesis a report on experimental work aiming for a better understanding of the mechanisms underlying Ewing sarcoma metastasis is presented. Two distinct mechanisms are investigated: (1) a biochemical approach in which the initial steps in the CXCR4 signaling cascade are followed, and (2) a biophysical approach in which the guidance of Ewing sarcoma metastasis by the stiffness of their microenvironment is demonstrated. The results presented in this thesis provide deeper insights into the mechanisms controlling signaling of the chemokine receptor CXCR4 and into the role of the micro-environment in Ewing sarcoma cells behavior.Through various experimental approaches it was shown that both biochemical and biophysical guidance control how Ewing sarcoma develops into its distinct metastatic phenotype.
- Published
- 2015
50. In vivo modelling of Ewing sarcoma in zebrafish
- Author
-
Ent, W. van der, Hogendoorn, P.C.W., Spaink, H.P., Snaar-Jagalska, B.E., Mummery, C.L., Dijke, P. ten, Hertog, J. den, Szuhai, K., and Leiden University
- Subjects
Anti-cancer drug screen ,Xenograft model ,Transgenic animal model ,High-throughput ,Zebrafish - Abstract
Ewing sarcoma (EWS) is a disease with a high need for novel therapeutic strategies. To aid in investigating such compounds in an in vivo setting, we have developed several zebrafish model systems for EWS, which are presented in this thesis. The first is a manual xenograft model in 2-day-old zebrafish embryos, in which cell behaviour on the level of proliferation and migration has been described, as well as their interaction with the host innate immunesystem. With this model, we found that simultaneous induction of the p53 pathway and disruption of EWS-FLI1 transcriptional activity had an additive effect on the reduction of EWS malignancy in vivo. The same model was used to explore the mechanism of NOTCH-induced tumour suppression, via Sirtuin1 (SIRT1) inhibition. In addition to this manual xenograft model, we also established a high-throughput automated implantation model in blastula stage embryos. Furthermore, a flexible transgenic model has been developed, where human EWSR1-ERG expression has been placed under an UAS promoter, allowing the gene to be expressed in different tissues at different times. When this EWS-driving fusiongene was expressed neuronally, overlap in gene and protein expression was found with other EWS models, as well as a histologic similarity to EWS tumours.
- Published
- 2015
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