Erik de Bakker
Hypergranulatory tissue in breast implant surgery and skin scar formatio
Thesis defense: 24-02-2023
Promotor: Prof.dr. M. Ritt, prof.dr. S. Gibbs. Copromotor: Dr. F.B. Niessen
Maarten Witte is group leader in the Department of Molecular Cell Biology & Immunology and part of the MS center Amsterdam. Throughout his career, he has been fascinated by the interplay between perhaps the two most complex systems in the human body, the immune and central nervous system (CNS), and how neuroinflammation contributes to neuronal damage in neurological diseases. Supported by grants from the US Department of Defense, Institute of Chemical Immunology (NWO) and an MS fellowship from the Dutch MS research foundation, his group aims to elucidate the immunological mechanisms that drive neurodegeneration in several neurological diseases, in particular multiple sclerosis (MS). To disentangle these neurodegenerative pathways, they study human post-mortem tissue and various in vitro and in vivo model systems using both state-of-the-art microscopy and single cell approaches.
Although the central nervous system has traditionally been defined as ‘immune-privileged’, research over the last decades has taught us that there is considerable interaction between the peripheral immune system and the brain in both health and disease. Similarly, we have come to appreciate that CNS-resident immune cells, particularly microglia, are not only involved in protecting the brain from pathogens and clearing debris, but play multiple critical roles in development, homeostasis and degeneration of the CNS.
Here, we aim to identify which infiltrated peripheral immune cell subsets drive neurodegeneration in progressive MS and to elucidate the mechanisms involved. We are particularly interested in the role of meningeal immune cells and how they might affect cortical microglia and neurons. Hopefully, this will allow us to identify novel therapeutic targets to stop neurodegeneration in progressive MS, which at present cannot be treated.
Recent literature suggests that direct, physical interaction between microglia and neurons is essential in maintaining neuronal function during brain homeostasis, and can be both neuroprotective and neurodegenerative under neuroinflammatory & neurodegenerative conditions. We aim to study cause and consequence of this physical interaction in health and disease by using newly developed photoactivatable ligands. These photochemical tools allow us to control the activation of individual microglia in vitro and in vivo and to subsequently assess the interaction between microglia and neurons.
My research focuses on understanding meningeal inflammation in progressive multiple sclerosis. I am specifically interested in the role of B cells, in how they get to the meninges and how they might interact, directly or indirectly, with other immune cells such as microglia. To do this, I use different single-cell techniques for proteomics and transcriptomics, and confocal and multispectral microscopy.
My research focuses on the role of B cell subsets in the pathogenesis of MS. I am especially interested in the involvement of the enigmatic innate-like B1 cell subset in the disease. Supported by the NWO 'mosaic' grant, I collaborate with the MCBI department to unravel the frequency, distribution, and function of B1 cells in MS and normal-aging brains. To this end, I investigate postmortem brains, blood, and CSF from MS and other neurodegenerative and neuro-inflammatory diseases.
Febe van Maldegem is group leader in the Department of Molecular Cell Biology & Immunology. Her work focusses on the complex role of the tumour microenvironment in non-small cell lung cancer (NSCLC), crucial for mediating anti-tumour immunity, but more frequently imposing resistance to therapy. Key to her work is the use of highly multiplex technologies, such as Imaging Mass Cytometry with which the tumour microenvironment can be studied in great detail, revealing the activation states as well as the spatial context of the many cells within the tissue. Febe van Maldegem’s research program, supported by award of the Amsterdam UMC fellowship, aims to improve therapeutic options for patients with non-small cell lung cancer by rationalising the design of combination, mindful of the important role for the tumour microenvironment in determining success.
The NSCLC TME as biomarker and therapeutic target
In order to understand how we can manipulate the TME to benefit therapeutic strategies, we will first need to better understand the dynamics within this complex system. This research line asks the basic questions: How does the TME evolve over time during tumour development, and what are the selective forces that drive this evolution? In several in vivo models for non-small cell lung cancer we study the changes in TME composition, at early time points from tumour onset into advanced tumour stages and under different experimental conditions. Imaging Mass Cytometry will provide detailed phenotypic and spatial characterisation of the cellular relationships in the tissue. The resulting spatial TME profiles will be used to generate biomarkers for response to therapy and to design novel therapeutic targets aimed at disrupting or enhancing cellular interactions.
Video, sequentially highlighting 15 out of the 27 markers this small lung tumour was stained for using Imaging Mass Cytometry (CX3CR1, PECAM, aSMA, EPCAM, B220, CD103, LY6G, CD8, CD4, CD11c, CD68, F480, CD45, CD44, MHC-II)
Rationally combining chemoradiotherapy with immune checkpoint inhibitors (ICI)
Neoadjuvant (chemo)radiotherapy (CRT) is the current standard of care for low grade NSCLC, but the field is moving towards combinations with ICI. Chemotherapy and radiotherapy can benefit immune responses by inducing immunogenic cell death, but can also be toxic to the immune cells. We will assess the impact of this treatment combination by analysing patient samples from current clinical trials, comparing different combinations of these therapies in pre- and post-treatment biopsies. In vitro and pre-clinical studies will be used to optimise the treatment dosing and scheduling, to provide a rational basis for design of the next generation of clinical trials.
Mugarza E*, van Maldegem F*, Boumelha J*, Moore C, Rana S, Sopena ML, East P, Ambler R, Anastasiou P, Clavijo PR, Valand K, Cole M, Molina-Arcas M, Downward J. Therapeutic KRASG12C inhibition drives effective interferon-mediated anti-tumour immunity in immunogenic lung cancers. Science Advances, 2022 July 22;8. doi: 10.1126/sciadv.abm8780
Van Maldegem F, Valand K, Cole M, Patel H, Angelova M, Rana S, Colliver E, Enfield K, Bah N, Tsang VSK, Mugarza E, Moore C, Hobson P, Levi D, Molina-Arcas M, Swanton C, Downward J. Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry. Nature Communications. 2021 Oct 8;12. doi: 10.1038/s41467-021-26214-x
van Maldegem F, Downward J. Mutant KRAS at the Heart of Tumor Immune Evasion. Immunity. 2020 Jan 14;52(1):14-16. doi: 10.1016/j.immuni.2019.12.013
Molina-Arcas M, Moore C, Rana S, van Maldegem F, Mugarza E, Romero-Clavijo P, Herbert E, Horswell S, Li LS, Janes MR, Hancock DC, Downward J. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019 Sep 18;11(510):eaaw7999. doi: 10.1126/scitranslmed.aaw7999
van Maldegem F, Maslen S, Johnson CM, Chandra A, Ganesh K, Skehel M, Rada C. CTNNBL1 facilitates the association of CWC15 with CDC5L and is required to maintain the abundance of the Prp19 spliceosomal complex. Nucleic Acids Res. 2015 Aug 18;43(14):7058-69. doi: 10.1093/nar/gkv643
The focus of my research is rationalizing and optimizing the combination of (chemo)radiotherapy and immunotherapy for the treatment of non-small cell lung cancer. For this, it will be crucial to enhance our knowledge about the effect of the therapies on the cells infiltrating the tumor microenvironment and their spatial context - and vice versa. Imaging Mass Cytometry will provide this in depth spatial and phenotypic characterization of the components of the tumor microenvironment.
My works focuses on the evolution of tumor microenvironment.I investigate the changes in TME composition from early time points to advanced stages and under different experimental conditions with in vivo model. Imaging Mass Cytometry will provide detailed phenotypic and spatial characteristic of the cellular relationships in the tissue.