Onderzoek

De research op de afdeling Pathologie is een combinatie van een translationeel en meer basaal onderzoek. Vooral bij het translationeel onderzoek heeft de afdeling Pathologie een spilfunctie binnen het AMC. Het wetenschappelijk onderzoek van de afdeling is ondergebracht in de volgende researchlijnen:

Cardiovascular Pathology

Prof. dr. M.J.A.P. Daemenpathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Prof. dr. A.C. van der Walpathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam

Research program prof. dr. M.J.A.P. Daemen

One part of the research focusses on mechanisms and imaging of plaque stability. Rupture of an atherosclerotic plaque is the main cause of the clinical symptoms of cardiovascular diseases such as acute myocardial infarction and ischemic stroke. For a ‘plaque at risk’, the risk of rupture is determined by morphological, molecular, biological and biomechanical parameters of the plaque. Focusing on the carotid artery, the ParisK consortium will construct technological and translational platforms in which several novel imaging modalities will be advanced, validated and added to existing non-invasive imaging modalities to measure one or more parameters of plaque at risk. The data will be integrated to develop a novel heuristic algorithm that gives the predicted risk of rupture of an individual plaque, which will be validated in subsequent clinical studies.

The novel fundamental aspects of the CTMM project ParisK (plaque at Risk) are:

1) Advanced Molecular Imaging: The three different targets of plaque vulnerability are: a) fibrin, which is related to blood clotting, b) macrophages that are related to inflammation and c) neovascularization, which can cause leakage of red blood cells into the plaque and destabilize it. Methods will be developed to target contrast agents at these markers so that they can be imaged by MRI, ultrasound and/or PET-CT. Detection methods for neovascularization will also be developed based on clinically-approved non-targeted contrast enhanced MRI and ultrasound.

2) Biomechanics: Ultimately, plaque rupture is a strictly mechanical phenomenon. If the forces exerted exceed the strength of the cap, it will break. Extensive measurement and modelling to assess both stress and strength will therefore be part of the project.

3) Clinical validation of optimized and new imaging modalities, multi-modal integration and development of a plaque-at-risk algorithm: Optimized and new imaging modalities will be integrated into a platform of state-of-the-art traditional imaging methods such as MRI, CT and ultrasound. Two clinical studies will be performed. In the first, the newly developed and optimized imaging technologies will be validated. In this study, patients will be included who have more than 70% stenosis of the carotid artery that requires surgery. This will allow measurements to be directly related to the actual composition of the plaque. In the second study, 300 patients will be included in a prospective follow-up study to evaluate the predictive power of traditional and novel imaging technologies.

A recently added part of the research program focusses on the heart and brain connections. While both cardiovascular disease and progressive loss of cognitive functioning are prominent features of an ageing population, surprisingly few studies have addressed the link between the function of the heart and extracranial arteries on the one hand, and the brain on the other hand. Yet recent data indicate that despite the capacity of the brain to adapt cerebral blood flow to its own demand, systemic hemodynamic changes that are a function of heart, aorta and cerebropetal arteries may reflect on the cognitive functioning. In the current research proposal we will test the hypothesis that the combined effects of cardiac and large vessel diseases are important and potentially reversible, but underestimated causes of vascular cognitive impairment offering an excellent opportunity for treatment. In a true multidisciplinary and translational approach we will test this hypothesis by analyzing available epidemiological data sets, perform new cross sectional and longitudinal studies in elderly patient populations and analyze and complement the data of a large epidemiological cohort with either vascular cognitive impairment, cardiac dysfunction, or carotid artery disease and evaluate the systemic and cerebral hemodynamic status with MRI and thoroughly test cognitive dysfunction. Animal studies will be used to dissect the mechanisms involved and to reveal novel leads for interventions.

Genetic alterations and gene expression profiles of solid tumors

Prof. dr. M.J. van de Vijver, pathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam

The research in our group is aimed at the use of genetic techniques to refine classification of solid tumors, with an emphasis on breast cancer, ovarian cancer and pancreatic cancer.
Breast cancer is presently classified based on tumor diameter, histologic type and grade, lymph node status and estrogen receptor, progesterone receptor and HER2 status. This classification has important implications for the treatment of breast cancer patients.

A more refined classification should be possible based on genetic alterations and gene expression profiles.
The genetic alterations identified in breast cancer are amplification of between 10 and 20 oncogenes and mutations in several tumor suppressor genes.
We have previously studied the genetic alterations (with a focus on HER2 gene amplification) in breast carcinomas in relation to clinical and pathological parameters.

Gene expression profiling has led to the identification of subsets of breast cancer revealed by unsupervised and supervised classification.
We have used supervised classification to identify a 70 gene prognosis profile and clinical studies are ongoing to investigate if and how this prognosis profile can be implemented in clinical practice.

The main projects on breast cancer are the identification of genetic alterations and gene expression profiles that are associated with pattern of metastasis and response to chemotherapy in patients with metastastatic breast cancer; and through participation in the EU funded BASIS project to identify genetic alterations in breast cancer in relation to histopathological features using whole genome sequence analysis and detailed histological analysis if breast carcinomas.

In ovarian cancer and pancreatic cancer we are studying heterogeneity of genetic alterations and gene expression profiles; and association with prognosis and response to therapy.


Immuno- and Hematopathology

Prof. dr. C.J.M. van Noesel, pathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Prof. dr. S.T. Pals, pathologist, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Dr. M. Spaargaren, P.I., department of Pathology, Academic Medical Center, University of Amsterdam
Research program dr. M. Spaargaren

Dr. Marcel Spaargaren is a medical molecular biologist at the Dept. Of Pathology, with a special interest in the molecular and cell biological aspects of the pathogenesis of B-cell malignancies, in particular multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), and the exploitation of this knowledge for clinical applications.
As a PI in the AMC, he participates in the major research themes “Oncology” and “Immunity and Infection” and as such in the Oncologic Research Center AMC (ORCA) and the Center for Immunology Amsterdam (CIA). He is dean of the Oncology Graduate School Amsterdam (OOA: Onderzoekschool Oncologie Amsterdam) for PhD students of the Netherlands Cancer Institute (NKI), Free University Medical Center (VUMC), and AMC. He is secretary of the society on Tumor Cell Biology of the Dutch Cancer Society (KWF-werkgemeenschap Tumorcel biologie), and co-founder and board-member of the Lymphoma and Myeloma Center Amsterdam (LYMMCARE).The research group of Marcel Spaargaren (Dept. of Pathology, section Immuno- and Hematopathology) has a long-standing interest in the molecular and cellular biology of B-cell differentiation and function, and in the pathogenesis of B-cell malignancies, in particular multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL).
The major themes of the current research are "Growth and differentiation of normal and malignant B cells" and "Cell adhesion and migration in immunity and cancer". In this context, the aims are: 
1) identify and molecularly dissect the signaling pathways involved in differentiation and function of B-cells and in the pathogenesis of B-cell malignancies; 
2) explore and exploit the microenvironment-dependence as the Achilles’ heel of B-cell malignancies, focussing on multiple myeloma and chronic lymphocytic leukemia.General interests include signal transduction, cell proliferation and survival, cell adhesion and migration, and tumor-microenvironment-dependence. More specifically, related to the differentiation and function of B cells and the pathogenesis of B-cell malignancies, they explore(d) the molecular and functional aspects of signalling by the B-cell antigen receptor, chemokines (e.g., CXCL12), HGF/MET, and WNTs, and the role of heparan sulfate proteoglycans (e.g., CD44 and Syndecan-1), adhesion molecules (integrins and cadherins), GTPases (e.g., Ras and Ral), kinases (e.g., Bruton’s tyrosine kinase), and transcription factors (e.g., FOXP1).

Neuropathology

Prof. dr. E.M.A. Aronica, neuropathologist, PI, Department of Pathology, Academic Medical Center, University of Amsterdam

Research program Prof. dr. E.M.A. Aronica:

  • Epilepsy
  • Inflammation
  • Neurodevelopmental disorders
  • Brain development and ageing
  • Neuroncology

Neuron-glia interactions in health and disease
Recent work on neuro-glial cell physiology has revealed that glial cells are much more actively involved in brain information processing than previously anticipated. This finding has stimulated the novel view that the brain should be viewed as a circuit of interactive neuron and glial cell networks. Despite the solidity of the evidence for glia-neuron signalling many fundamental questions on the basic cellular and molecular aspects of this intriguing partnership still remain unanswered or have not been addressed in the functional in vivo context. The major aim of our research efforts is to investigate the role of glial cells as potential cellular targets for developing novel therapies in human neurological disorders. To achieve this aim we use a multidisciplinary approach, creating a collaborative team of specialisms including neurology, neuropathology and neurobiology. In 2006 we performed large-scale studies of gene expression using experimental models and human material from patients with acute and chronic CNS injury. We provided evidence of a prominent and persistent activation of the innate immune response in various neurological disorders with different etiologies, but without a primary inflammatory pathogenesis. This response involves both astrocytes and microglial cells and is associated with the activation of several pathways which influence hyperexcitability, degeneration and regeneration.

In 2007, international collaborations have been established to further investigate the role of astroglial and microglial cells in the initiation and persistence of the inflammatory response associated with neuronal degeneration and hyperexcitability (Grant of the European Union: HEALTH-2007-2.2.1-6:“ Neuron-glia interactions in health and disease”; www.neuroglia.eu ). This has been investigated in human brain and in well established animal models of epilepsy. 

In collaboration with the group of Dr. Vezzani (Mario Negri Institute, Italy) we recently reported a proconvulsant pathway involving high-mobility group box-1 (HMGB1) release from neurons and glia and its interaction with Toll-like receptor 4 (TLR4), a key receptor of innate immunity. HMGB1-TLR4 signaling may contribute to generating and perpetuating seizures in humans and might be targeted to attain anticonvulsant effects in epilepsies that are currently resistant to drugs (Nature Medicine, 16: 413–419, 2010).

We are presently studying the role of proinflammatory signaling-associated microRNAs (miRNA). As described in the recently article published in EJN (Eur J Neurosci.; 31(6):1100-7. 9) we demonstrated in both experimental and human temporal lobe epilepsy the selective up-regulation of the on miR-146a, a microRNA that is induced by pro-inflammatory stimuli, modulating innate immunity through regulation of Toll-like receptor signaling. 

New projects starting in 2012:

1. 2012-2015: Grant of the European Union: HEALTH.2011.2.2.2-2 " Pathways common to brain development and ageing: defining strategies for preventive therapy and diagnostics “

Objectives

a. To examine neurodegeneration-related proteins during development: comparing early and postnatal developmental stages in developmental disorders

b. To examine the relationship between neurodegeneration-related proteins and specific developmental pathway. 

c. To study selected altered mRNAs, microRNAs and proteins in focal cortical malformations

2. 2012-2016: Characterization of genetic aberrations in pediatric low-grade glioneuronal tumors Stichting Kinderen Kankervrij (KiKa).

The aim of the study is to identify chromosomal changes in an international large series of GNT’s by genomic wide microarray based comparative genomic hybridization (aCGH), PCR and genomic sequencing. During the project these chromosomal changes will be investigated for their potential clinical relevance as related to prognosis, pathogenesis en epileptogenesis. The miRNA profile of GNT’s will be also evaluated. By investigating these biologic characteristics in relation to the clinical data, we can improve the diagnostics and therapy for GNT’s in children, as guided by the clinical biological risk profile of the tumor.

Renal pathology

Prof. dr S. Florquin, Renal Pathologist, P.I., Department of Pathology, Academic Medical Center, University ofAmsterdam 

Sandrine Florquin (1965) received her MD degree from the Faculty of Medicine of the Universite Libre de Bruxelles (Belgium) in 1990, her “Thèse d’Agrégation de l’Enseignement Supérieur”from the same University in 1995, and her PhD degree (cum laude) from the University of Leiden (The Netherlands) in 1997. In 1998 she was board certified in the Netherlands in Pathology, and in 2001 in Immunology. From 1991 to 1994, she was Research Fellow of Fonds National de la Recherche Scientifique(Belgium) in the department of Immunology of Prof. M. Goldman, Université Libre de Bruxelles and in the departments Prof. B. Brenner and R. Cotran (Brigham and Women’s Hospital, Harvard University). Since 1998 Florquin is staff member of the Department of Pathology in het AMC. Her research is embedded in the Center for Immunology Amsterdam (CIA). She received several NWO-grants (Clinical Fellowship, ASPASIA and VIDI). In 2007 she was appointed Professor of Pathology in theUniversity of Amsterdam. She is a member of the Scientific Board of the Dutch Kidney Foundation and of the ERA-EDTA.

Research Programs: Renal Inflammation and REpair (RIRE)

Thanks to the financial support of NWO and Dutch Kidney Foundation, we set up a research group dedicated to unravel the immunological mechanisms involved in renal injury and repair and to design new therapeutic tools for renal diseases.

To unravel the involvement of innate immunity in the renal diseases, we used relevant rodent models for acute and chronic renal injury (ischemia-reperfusion, obstructive nephropathy, renal transplantation and pyelonephritis using knock-out mice, transgenic mice, anti-sense oligonucleotide and blocking antibodies), renal biopsies, urine and plasma of renal patients, and in vitro models (tubular epithelial cell and endothelial cell cultures).

Our research line can be divided in 4 sub-themes:

a) The role of CD44 in Renal Injury and Repair
b) The role of Pattern-Recognition Receptors (PRRs) in Renal Injury and Repair
c) The fibrinolytic and clotting systems in Renal Injury and Repair
d) Development of validated analyses of renal transplant biopsies to identify local markers
of tolerance and to predict the development of fibrosis

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