The research within our LUMC departments is conducted within departmental research programmes. The research programme below is embedded within the department of Chemical Cell Biology / Chemical Immunology.
Aim and focus
The aim is to integrate chemistry and cell biology in an internationally unique research program. The focus is on a number of different enzyme classes in that are relevant in oncology, immunology and cell differentiation and more generally in cell biology. More specifically we focus on DUBs, kinases, phosphatases and esterases that in total cover many of the enzyme activities in cells. We will develop tools to visualize these activities in vitro and in cells and also use probes in drug screening programs.
This defines the second aim of the department; identifying and improving drugs active in a series of diseases, in particular oncology. By studying the cell biology of anthracycline anti-cancer drugs, we improve these drugs especially by eliminating devastating side effects. One drug is now made at clinical grade and will be reintroduced in the clinic early 2017 and two drugs are in the pipeline of drug development.
We are also studying the cell biology of endosomal transport with the aim to understand and manipulate endocytosis but also associated processes and phagocytosis. This is a broad program including again the chemical tools generated in this research program. In addition, this program has many links to other programs within LUMC including signalling, MHC class II associated antigen presentation and bacterial infections.
Finally, we are also studying whether bacterial infection predispose cells to transformation. This research program is a result from our cell biological studies on endosomes and phagosomes. This research program combines laboratory experiments and epidemiology to both show correlation and causality of the involvement of bacterial infections in cancer. We are currently studying bacteria that are associated with food poisoning and are expanding these to other bacterial species.
In summary, the Department of Chemical Immunology combines both chemistry and cell biology/immunology experiments unique in both disciplines with impact for many fields and translation already in the field of oncology.
Position in international context
We are the first Department of Chemical Immunology in the world. This has been based on a successful Gravity program called ‘Institute of Chemical Immunology’ (ICI) that was funded in 2014. The labs and work space of the chemists and cell biologists are mixed to ensure optimal interactions and ‘cross-over experiments’, and is –again- considered by visiting colleges as unique. The Department of Chemical Immunology includes two labs and both labs have a strong international position and collaborate with the other leaders in the fields resulting at a series of top publications in journals like Cell and Nature. The Department is also strongly linked to the Bio-organic Chemistry faculty at the Science Faculty in Leiden and various joint programs are running to use more interesting compounds for cell biology and translation in oncology. The Department thus acts as an inter-faculty intermediate, which is again unique in the world.
Content / highlights / achievements
Ovaa has been an ERC awardee and got the KNCV golden medal and the NVBMB award 2008. He is Editor of Cell Chemistry. Neefjes has been awarded an ERC Advanced grant twice (2012 and 2016). He was also awarded the KNCV golden medal and the van Loghem lecture (the career award of the Dutch Society of Immunology) in 2015. Neefjes has been member and chairman of the scientific board of the Dutch Cancer Society KWF and is chairman of the scientific council of the Children Oncology Fund KiKa. He is also member of the COST Action program scientific board in Brussel and has various other organization activities.
The Department has published many outstanding publication in top journals (see under 7). The scientific output is both significant and extensive. Various breakthrough have been reported by the Department over the years that can be considered highlights.
Scientific highlights of the last years include:
- First causal definition of the role of bacterial infections in oncology (Scanu et al., 2015)
- Identification of a new activity of the old anti-cancer drug doxorubicin (Pang et al. 2015)
- First ubiquitin ligase probe developed (Mulder et al, 2016)
- Identification of a new inhibitor activity mechanism in inhibitors (Hekkebus 2013)
- Role of cysteine catalyses in the process of RING domain catalyses (Scott et al., 2016)
- Identification mechanism of endosome positioning in cells (Jongsma et al, 2016)
- Jongsma ML, Berlin I, Wijdeven RH, Janssen L, Janssen GM, Garstka MA, Janssen H, Mensink, M, van Veelen PA, Spaapen RM, Neefjes J. (2016) An ER-Associated Pathway Defines Endosomal Architecture for Controlled Cargo Transport. Cell. 166(1):152-66.
- Scanu T, Spaapen RM, Bakker JM, Pratap CB, Wu LE, Hofland I, Broeks A, Shukla VK, Kumar, M, Janssen H, Song JY, Neefjes-Borst EA, te Riele H, Holden DW, Nath G, Neefjes J. (2015), Salmonella Manipulation of Host Signaling Pathways Provokes Cellular Transformation, Associated with Gallbladder Carcinoma. Cell Host Microbe.17(6):763-74
- Paul P, van den Hoorn T, Jongsma ML, Bakker MJ, Hengeveld R, Janssen L, Cresswell P, Egan DA, van Ham M, Ten Brinke A, Ovaa H, Beijersbergen RL, Kuijl C, Neefjes J. (2011) A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation. Cell. 145(2):268-83
- Zhang X, Smits AH, van Tilburg GB, Jansen PW, Makowski MM, Ovaa H, Vermeulen M. (2017) An Interaction Landscape of Ubiquitin Signaling. Mol Cell. 65(5):941-955.
- Mevissen TE, Kulathu Y, Mulder MP, Geurink PP, Maslen SL, Gersch M, Elliott PR, Burke JE, van Tol BD, Akutsu M, El Oualid F, Kawasaki M, Freund SM, Ovaa H, Komander D. (2016) Molecular basis of Lys11-polyubiquitin specificity in the deubiquitinase Cezanne. Nature. 538(7625):402-405.
- Mulder MP, Witting K, Berlin I, Pruneda JN, Wu KP, Chang JG, Merkx R, Bialas J, Groettrup M, Vertegaal AC, Schulman BA, Komander D, Neefjes J, El Oualid F, Ovaa H. (2016) A cascading activity-based probe sequentially targets E1-E2-E3 ubiquitin enzymes. Nat Chem Biol. 12(7):523-30.
- Flierman D, van der Heden van Noort GJ, Ekkebus R, Geurink PP, Mevissen TE, Hospenthal MK, Komander D, Ovaa H. (2016) Non-hydrolyzable Diubiquitin Probes Reveal Linkage-Specific Reactivity of Deubiquitylating Enzymes Mediated by S2 Pockets. Cell Chem Biol. 23(4):472-82.
- Geurink PP, van Tol BD, van Dalen D, Brundel PJ, Mevissen TE, Pruneda JN, Elliott PR, van Tilburg GB, Komander D, Ovaa H. (2016) Development of Diubiquitin-Based FRET Probes To Quantify Ubiquitin Linkage Specificity of Deubiquitinating Enzymes. Chembiochem. 17(9):816-20.
- Pang B, de Jong J, Qiao X, Wessels LF, Neefjes J. (2015) Chemical profiling of the genome with anti-cancer drugs defines target specificities. Nat Chem Biol. 11(7):472-80.
- Pang B, Qiao X, Janssen L, Velds A, Groothuis T, Kerkhoven R, Nieuwland M, Ovaa H, Rottenberg S, van Tellingen O, Janssen J, Huijgens P, Zwart W, Neefjes J. (2013) Drug-induced histone eviction from open chromatin contributes to the chemotherapeutic effects of doxorubicin. Nat Commun. 4:1908.
- The chemical immunology program will continue as the Gravity program is financially supported for at least 6 years. The interesting point of Chemical Immunology is that the result does not follow standard technologies, in fact chemical solutions to almost every individual problem have to be developed and this development is only beginning to be explored. The translation of this work is getting in an interesting phase where some of the lead structures are further developed towards clinical introduction in oncology. One drug is being made to introduce in the clinic early 2017 and two drugs are further developed for clinical testing. We expect more of these developments in the near future, especially when the integration of the various faculties involved in the different aspects of drug development and exploration is succeeded. We expect that some more work in direct connection with the clinic will be developed in relation to the clinical testing of LUMC-made drugs.
- The Department has developed a new drug screening pipeline and we expect new bioactive entities identified and some of these further developed in the future. We will integrated biology and chemistry to define better drugs and we are making attempts for more structural funding of this drug identification pipeline.
- We expect the identification of new bacteria involved in the induction of cancer. This is a unique line of research, especially with the integration of epidemiology. We expect that this line of research will develop further in the future with new pathogens identified in new cancer. Such tumors can then be prevented by better health care measures.
- Finally, we expect many new finding related to the molecular mechanisms controlling the endosomal system. This is an important field as most pathogens highjack this system to enter hosts. In addition, many neurological diseases are based on malfunctioning endosomes and we aim to define the molecular basis of this process with the hope to define molecules able to correct the different neurological defects.
In summary, we expect to further develop the chemical biology of the department with the aim to both increase our molecular understanding of various diseases and anti-cancer drugs and to translate that with the development and introduction of some drugs in the clinic for better treatment options of (in these cases) cancer patients.
Cohesion within LUMC
Biomedical research profiles:
- Cancer Pathogenesis and Therapy
- Immunity, Infection and Tolerance