Leiden University

Leiden Amsterdam Center for Drug Research (LACDR)

 

Contact

Erik Danen
e.danen@lacdr.leidenuniv.nl
Thomas Hankemeier
hankemeier@lacdr.leidenuniv.nl

 

Added value Leiden University for hDMT: 

• Expertise in microfluidics and medium/high throughput organ-on­-a­-chip assays
• Expertise in 3Dculture
• Expertise in cell-­ECM interactions and implications for cell fate
• Fluorescence microscopy facility with automated high content high throughput confocal imaging and quantitative image analysis
• Expertise in drug/RNAi screening
• Expertise in metabolomics and systems pharmacology for translational research:from patients to organ-on-a-­chip,and back

 

Added value hDMT for Leiden University:

• Dutch interaction network microfluidics
• Dutch interaction network 3D culture systems
• Innovative models for drug development
• Speed up development of new human­-relevant in vitro models for drug (target) discovery
• Expertise on drug efficacy and safety assessment

 

Expertise and facilities:

Expertise

• Large­scale development of 3D cell culture models and advanced microfluidics systems
• Screening by RNAi and chemical libraries
• Metabolomics and high content imaging (Netherlands Metabolomics Center/NL Bioimaging node High Througput Microscopy (HTM) and EU Bioimaging node HTM).
• Central role within University of Leiden in drug research and development, in close collaboration with LUMC and CHDR
• Automated medium-throughput screening on advanced 3D Organ on chip models

Facilities

• Leiden Cell Observatory: 3X automated confocal imaging systems with perfect focusing and automated stage (Nikon); multiphoton imaging (Nikon); BD Pathway 855 with robotics and automated cell culturing automated liquid handling BIOMEK with robotic cell culturing
• Cell culture laboratories; MLII facilities automated FACS
• High throughput multiparameter image analysis pipeline (RHDF2, Cell Profiler and R)
• siRNA libraries for entire druggable human genome; compound libraries for all FDA approved drugs.
• Metabolomics and mass spectrometry facility for biochemical profiling of organ-­on­-a­chip systems
• Systems Pharmacology models and algorithms including PK/PD, reconstructed metabolic networks, biomarker discovery, and translational algorithms
• Rapid prototyping facility to produce custom­made microfluidic devices

 

Ongoing projects:

• Microvascular system in OrganoPlates: A microvascular model is developed in different tissue contexts to study the influence of microvasculature on organ damage, and using metabolomics techniques to study disease mechanism and pharmacology (ABS/LACDR with MIMETAS &LUMC(Van Zonneveld/Mummery)PIs Hankemeier/Vulto).
Chemotherapeutic combination therapy screening on cancer stem cell spheroids: Aim of the project is the development of an organotypical model consisting of intestinal tumor stem cell spheroids that are grown in 3D in an ECM (vasculature added). The models are screened for effectivity of different chemotherapeutics in combination with pump inhibitors (ABS/LACDR collaboration with MIMETAS & UMCU; PIs Hankemeier/Vulto).
LgR5+ gut epithelial organoid culture in low volumes: Aim of the project is to screen intestinal gut organoids in minimal volumes and study boundary formation (ABS/LACDR with MIMETAS & Hubrecht Lab; PIs Hankemeier/Vulto).
Neuronal co-cultures in microfluidic plates, and metabolomics for functional studies of disease genes for Alzheimer (LACDR with Mimetas and Erasmus MC Kushner/Van Duijn); PIs Hankemeier/Vulto; funding EU, pharma).
• Metabolomics of organ-on-chip system of pancreatic cancer (ABS/LACDR with Mimetas; PIs Hankemeier/Vulto, funding: EU)
Arrayed 3D ECM-embedded spheroids for multiple cancer types for drug screens (PI EHJ Danen; funding KWF & LU; collaboration NKI & LUMC).
3D ECM-embedded tumor spheroids for studies on tumor angiogenesis and physical aspects of ECM organization in this process (PI EHJ Danen; funding KWF & FOM; collaboration Physics Institute Leiden & AMOLF).
Systems microscopy for high content RNAi screens (PI B van de Water; funding EU FP7; collaboration Karolinska Institute and Weizmann Institute)
A 3D liver model for in vitro toxicity studies (PI B van de Water/L Price; funding NGI/NTC; collaboration OcellO)
Fluorescent reporter cell models to study signalling and adaptive stress responses (PI B van de Water; funding Pharma & EU FP7)

 

Publications

• Ghotra, V.P.S., He,S., van der Horst, G., Nijhoff, S., de Bont, H., Lekkerkerker, A., Janssen, R., Jenster, G., van Leenders, G.J.L.H., Hoogland, A.M., Verhoef, E.I., Baranski, Z., Xiong, J., van de Water, B., van der Pluijm, G., Snaar­-Jagalska, B.E., Danen, E.H.J.. SYK is a candidate kinase target for the treatment of advanced prostate cancer. Cancer Res 2014 in press.
• Truong, H.H, Xiong, J, Ghotra, .V.P, Nirmala, E., Haazen, L., Le Dévédec, S.E., Balcioglu, H.E., He, S., Snaar­Jagalska, B.E., Vreugdenhil, E., Meerman, J.H., van de Water, B., Danen, E.H. 1 integrin inhibition elicits a prometastatic switch through the TGF­miR­200­ZEB network in E­cadherin­positive triple­negative breast cancer. Science Signaling 7 (312): ra15 (2014).
• Di, Z, Klop, M.J., Rogkoti, V.M., Le Dévédec, S.E., van de Water, B., Verbeek, F.J., Price, L.S., Meerman, J.H. Ultra High Content Image Analysis and Phenotype Profiling of 3D Cultured Micro­Tissues. PLoS One 9 (10): e109688 (2014).
• Yizhak, K., Le Dévédec, S.E., Rogkoti, V.M., Baenke, F., de Boer, V.C., Frezza, C., Schulze, A., van de Water, B., Ruppin, E. A computational study of the Warburg effect identifies metabolic targets inhibiting cancer migration. Mol Syst Biol 10(20):744 (2014).
• Truong, H.H., de Sonneville, J., Ghotra, V.P., Xiong, J.P., Price, L., Hogendoorn, P.C., Spaink, H.H., van de Water, B., Danen, E.H. Automated microinjection of cell­polymer suspensions in 3D ECM scaffolds for high­throughput quantitative cancer invasion screens. Biomaterials 33:181­188 (2012).
• Trietsch, S.J., Israels, G.D., Joore, J., Hankemeier, T., Vulto, P., Microfluidic titer plate for stratified 3D cell culture. Lab on a chip, vol. 13, no. 18, pp. 3548­54.
• Vulto, P., Podszun, S., Meyer, P., Hermann, C., Manz, A., Urban, G.A. Phaseguides: a paradigm shift in microfluidic priming and emptying. Lab Chip, 2011, 11, 1596­1602.
• Quist J., Vulto, P., Van der Linden, H. J., & Hankemeier, T. Tunable Ionic Mobility Filter for Depletion Zone Isotachophoresis. Anal Chem 2012; 84: 9065­9071.
• Ellero­-Simatos, S., Lewis, J.P., Georgiades, A., Yerges­ Armstrong, L.M., Beitelshees, A.L., Horenstein, R.B., Dane, A., Harms, A.C., Ramaker, R., Vreeken, R.J., Perry, C.G., Zhu, H., Sànchez, C.L., Kuhn, C., Ortel, T.L., Shuldiner, A.R., Hankemeier, T., Kaddurah­-Daouk,R. Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability. CPT Pharmacometrics Syst Pharmacol. 2014 ;3: e125. doi: 10.1038/psp.2014.22.
• Schoonen, J.W., van Duinen, V., Oedit, A., Vulto, P., Hankemeier, T., Lindenburg, P.W. Continuous-­flow microelectroextraction for enrichment of low abundant compounds. Anal Chem. 2014: 86: 8048­8056.

 

Relevant patents

• Danen, EHJ et al. (2011) WO2012131000: Method for obtaining a multicellular spheroid.
• Leiden University and Mimetas hold a portfolio of patents related to the OrganoPlate™ and Phaseguide technology, which cannot be disclosed.
• Leiden University holds several patents related to miniaturized analytical methods enabling coupling mass spectrometry with organ­-on­-a-­chip systems.