Research Wim Vanden Berghe

Abstract

Iron plays a major role in cell homeostasis by regulating metabolism, respiration and DNA synthesis. Moreover, various cancer cells, such as multiple myeloma (MM), are addicted to increased iron levels as compared to their healthy counterparts to maintain rapid growth and proliferation. MM is a B-cell malignancy of malignant plasma cells in the bone marrow. Besides, iron plays an important role in the regulation of ferroptotic cell death, which makes iron metabolism an attractive therapeutic cancer target. We recently demonstrated that therapy resistant MM cells are highly sensitive to ferroptosis. Remarkably, we found that ferroptosis treatment triggers unique epigenetic changes in iron-specific histone modifications and chromatin remodeling proteins FOXA1 and NR4A1-3 which target genes involved in metal detoxification, cell cycle progression and DNA damage regulation. In this respect, I want to further elucidate iron-chromatin dependent epigenetic regulation ferroptosis therapy sensitivity in MM in vitro and ex vivo (blood, bone marrow) by i) demonstrating in vitro iron binding to recombinant histones, ii) assessing iron-histone binding-dependent ferroptosis therapy sensitivity, iii) assessing iron-histone-ferroptosis-dependent changes in chromatin accessibility and gene expression and iv) assessing single cell iron-histone-ferroptosis gene expression and antitumor immunity signatures in MM patient samples.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Driesen Amber

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

Due to global warming and increased sun exposure, skin cancer has a high incidence and increasing prevalence within the Cuban population. An extract obtained from the local marine plant Thalassia testudinum, rich in polyphenols, has shown effective photoprotection properties and antitumor activity against skin cancer. Until now, the extract production implicates the collection of the species from its natural habitat. However, such approach may endanger biodiversity and eco-sustainability as T. testudinum (known as turtle paste) nurtures other species and plays a central role in the coral reef-seagrass-mangrove ecosystem, which in turn protects the dune from extreme weather events, the coastal communities and the archipelago itself. To preserve the environment, ecological alternatives will be developed for efficient production of secondary metabolites facilitated by abiotic elicitors via bioreactor, tissue culture and plant biotechnology. The obtained biomolecules will next be conjugated to nanostructures to promote synergistic biological effects and to increase therapeutic efficacy. Altogether, environmental friendly and eco-sustainable production strategies will be developed for novel safe and effective pharmaceutical formulations from T. testudinum applicable in the prophylaxis of skin cancer, a serious health problem in Cuba. The overall goal is to strengthen training of gender balanced male and female researchers and build up institutional infrastructure capacities in blue (marine) and green (plant) biotechnology applications to improve health of the Cuban population and to stimulate sustainable eco-friendly circular bio-economy in Cuba. The uptake and outreach of the solutions here achieved may improve international visibility of local institutions, reinforcing global citizenship while education, access to scientific advancement and its benefits, health and human welfare (basic human rights) are improved.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Pieters Luc
• Co-promoter: Tuenter Emmy

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

The current application envisages extending the infectious disease and inflammation research and drug discovery platforms at the University of Antwerp to accommodate highly flexible and versatile live cell imaging and biochemical read-outs with a possibility to upgrade from median to high throughput. The apparatus will be embedded in a high-end immunoprofiling platform and BSL-2 environment at the Laboratory of Microbiology, Parasitology and Hygiene (LMPH) with biosafety approvals for basic research on infection with microbial pathogens. The TECAN SPARK Cyto 600 is a highly versatile multimodal plate reader that enables cellular and in situ molecular assays in controlled O2/CO2, humidity cassette and temperature regulation environments with real-time absorbance, fluorescence and luminescence measurements. Three different optical measurement options exist by using filters, monochromators or fusion optics which eliminates the compromise between sensitivity and flexibility. The unique lid-lifting function enables substrate addition or immune cell priming through the included 2-channel injector. SPARK Cyto 600 is equipped with 2×, 4× and 10× objective lenses and a CMOS camera to enable live cell imaging. In addition to bright field imaging, fluorescence imaging is possible in 4 optical channels with capability of Time-Resolved Fluorescence (TRF) and Fluorescence Resonance Energy Transfer (FRET). An additional asset is the compatibility with bead-based proximity assays using Alpha Technology with optimized integrated filters and laser-based excitation. While all known competitors limit live cell imaging systems to bright field and fluorescence measurements, the SPARK Cyto 600 also allows for real-time detection of glow and flash luminescence signals and Bioluminescence Resonance Energy Transfer (BRET) applications to enable sensitive real-time follow-up of protein-protein interactions in cells. Given the high versatility and pressing need for such equipment for infection and inflammatory disease research, this unique apparatus will allow real-time imaging of cellular as well as molecular events in controlled conditions. This new infrastructure will therefore boost research of many research groups at the University of Antwerp and will contribute to fundamental insights at the cellular and molecular level as well as to the development of novel therapeutics and diagnostics.

Researcher(s)

• Promoter: Caljon Guy
• Co-promoter: Augustyns Koen
• Co-promoter: Sterckx Yann
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Wullaert Andy

Research team(s)

• Laboratory for Microbiology, Parasitology and Hygiene (LMPH)

Project type(s)

• Research Project

Abstract

Epigenetic regulation has been shown to be involved in ferroptosis therapy resistance. Ferroptosis is increasingly recognized as a promising treatment option for cancer therapy, while diagnostic tools that predict tumor's sensitivity for ferroptosis are not yet developed. Therefore, in this industrial PhD project (Baekeland), a multi-step approach will be applied to (i) identify a "ferroptomics" epifingerprint that determine this ferroptosis sensitivity, (ii) develop a sensitive, cost-effective and portable nFERROCATCH assay to predict ferroptosis sensitivity based on TGS, one of the strongholds of OHMX.bio (precision diagnostics based on Nanopore sequencing) and (iii) validate the assay using experimental and clinical samples. This nFERROCATCH assay will be offered as a fee for service and can also be further commercialized.

Researcher(s)

• Promoter: Vanden Berghe Tom
• Co-promoter: Vanden Berghe Wim
• Fellow: Vintea Iuliana

Research team(s)

• Pathophysiology

Project type(s)

• Research Project

Abstract

Multiple myeloma (MM) is a B-cell malignancy characterized by the accumulation of a clone of malignant plasma cells in the bone marrow. Despite the progress in therapy, MM remains largely incurable. Conventional therapies with proteasome inhibitors (bortezomib), immunomodulatory drugs (thalidomide, lenalidomide), epigenetic drugs (Velcade), corticosteroids, and alkylating agents (melphalan) are associated with low remission rates, limited survival times (approx. 5 years) and the development of drug resistance. In the current project, pharmacological and biophysical (plasma) ferroptosis strategies will be optimized for MM chemosensitisation and/or immunogenic therapeutic approaches in MM cell lines (in vitro), MM patient samples (ex vivo) and preclinical MM mouse models (in vivo). In addition, a novel phospho-catalytic kinome activity mapping approach will be developed using biological peptide targets as phospho-sensors which allow kinome level quantification of redox specific changes in tyrosine kinase activities following ferroptosis chemosensitisation and/or immunisation in the different experimental therapeutic setups. Moreover, this phosphopeptide fingerprint can be applied as a diagnostic and/or predictive biomarker for personalized medicine applications for improved therapeutic outcome in MM patients

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Driesen Amber

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

The research activities of the consortium IPPON (Integrated Personalized & Precision Oncology Network) are at the forefront of integrated personalized cancer medicine, with emphasis on 1) developing novel and more effective therapeutic strategies; 2) an improved detection and understanding of mechanisms driving therapeutic resistance; and 3) identifying and validating biomarkers for early detection and personalized therapy, in different cancers in need for improved therapeutic outcomes. In this way, we aim to deliver the right treatment to the right cancer patient at the right time. Novel and emerging anticancer strategies that we investigate include - but are not limited to - locoregional perfusion, targeted therapy, immunotherapy, cold atmospheric plasma therapy as well as novel combination therapies. We are convinced that the interdisciplinary collaboration between basic, translational and clinical researchers, catalyzed through this consortium, will enable us to tackle burning research questions and clinical unmet needs to advance the field of personalized cancer medicine. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated clinical phase I/II oncological unit with a unique and complementary set of methods and skills covering the entire spectrum of molecular techniques, 2D and 3D cellular assays (in vitro and ex vivo), small- and large animal studies and clinical studies. IPPON gathers experts with an excellent research track record in fundamental, translational and clinical oncology; surgical techniques; targeted therapy; immunotherapy; (epi)genomics; (epi)transcriptomics; proteomics; imaging; liquid biopsies; pathology and clinical studies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Dewilde Sylvia
• Co-promoter: Hendriks Jeroen
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Smits Evelien
• Co-promoter: Van Dam Peter
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Protein phosphorylation is a reversible post-translational modification playing a crucial role in controlling the functional state of proteins in health and disease. Profiling protein kinase activity has become a critical component in molecular clinical biology precision medicine and constitutes a promising tool for drug discovery. However, current strategies can monitor only single kinases or imply complex procedures and infrastructure difficulting their assessment. The PPES platform performs parallel measurement(s) of kinase activities by recording phosphorylation changes in real time, revealing a more realistic view of the cellular signalling states and molecular mechanisms operating in disease and drugs mode of action. The PPES service facility for Global Kinase Activity profiling (https://www.kinases-epigenetics-ppes.com/) uses the Pamstation-12 (PamGene NVA, Netherlands), a fully automated instrument designed to process peptide microarrays (pamchips). This technology allows simultaneous measurement of multiple kinase activities (either activation or inhibition) through highly sensitive monitoring of the phosphorylation dynamics of 144 peptide substrates by Serine/ Threonine or 196 for Tyrosine kinases, present in (clinical) biosamples of interest (cells, tissues, organoids, ipscs, patients biopts). Our group has gained unique expertise in the profiling of kinase activity in a wide range of biological samples, including cell lines (glioblastoma, pancreatic cancer, neuroblastoma, multiple myeloma, T-cell acute lymphoblastic leukaemia, breast cancer), cells and patient-derived xenografts, patient-derived organoids, mouse, and human tissue samples (brain and colon), and patients' liquid biopsies. Moreover, the platform allows the "pharmacology on-chip" evaluation of kinase inhibitors that, together with the new systems biology core integrating kinome data with other omics techniques (e.g. transcriptome, phospho-proteome and epigenome data), will narrow the bridge between disease and drug discovery strategies. Our technology can be applied in a wide spectrum of fundamental, translational, diagnostic, and clinical research: a) Find novel targets, determine activities of kinase inhibitor drugs or novel food ingredients, and elucidate their mechanisms of action, b) to determine the mode of action of pharmacological compounds, c) to perform target interaction/ engagement studies, d) for Enzymatic characterization of novel or mutated kinases. e) for the identification of substrates for novel, mutated or post-translationally modified kinases, f) for prognosis and resistance Biomarker discovery and g) or evaluation of pharmacological drug dosage or combination therapy. In the frame of the IOF-service platform, we will setup a collaborative service with synergistic Biotech and ICT services to boost the knowledge gain from the initial (already running) platform. We will offer the service to academic research groups, clinical research labs as well as, drug screening, pharma, and biotech companies.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Van Laere Steven

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project website

Project type(s)

• Research Project

Abstract

Neurodegenerative diseases, including Alzheimer's disease (AD), are among the first causes of disability and early death in Europe and their prevalence and burden are expected to increase in its ageing population. Women are particularly vulnerable, probably due to their generally higher life expectancies. This comes with an enormous socioeconomic impact for AD patients, their relatives and caregivers. The pathophysiology of AD is complex and multifactorial, including amyloid brain deposition and tau hyperphosphorylation, but also metal dyshomeostasis, oxidative stress and neuroinflammation. Despite the remarkable number of drug candidates that have been evaluated in clinical trials for AD, almost all of them have failed to modify the progressive cognitive decline in patients. Together with the multifactorial nature of the disease, the poor translational potential of preclinical models in drug development for AD has been regarded as one of the major reasons for this failure. Therefore, the implementation of more TRANSlatable and characterized preclinical models for AD drug discovery and development is a must. Animal models have provided insightful mechanistic cues for the pathophysiology of neurological diseases. However, most in vivo models rely on transgenic mice that otherwise do not spontaneously develop pathophysiological hallmarks of AD. The advent of the induced pluripotent stem cells (iPSC) reprogramming technology allowed to obtain patient specific neural cells which spontaneously resembles traditional features of AD pathophysiology, when cultured in 2D and 3D systems. For instance, AD iPSC-derived neurons and astrocytes show elevated levels of Aβ42 and impaired trophic support, respectively. However, a number of promising other mechanisms has only recently been focused in AD patients and in vivo models, but have not yet been characterized in AD iPSC-derived neural cells. In my project TRANS4AD I aim to characterize novel functional and molecular features of human female AD iPSC derived neurons and astrocytes co-cultures (NACC) as a translational platform to evaluate innovative therapeutic candidates for AD. Particularly, we will look at differential kinome responses, ferroptosis vulnerability and functional neuronal integrative network connectivity in this co-culture system exposed to iron overload, and the influence that ferroptosis inhibitors might cause. In TRANS4AD I will apply cutting-edge high-throughput molecular signalling, electrophysiology and microscopy techniques, spanning different disciplines such as cellular and molecular biology, single cell droplet digital qPCR, neurophysiology, bioinformatics and neuroimmunology, in the multidisciplinary and innovative environment of the host labs at the University of Antwerp (UA) and Biogazelle as non-academic placement.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: García Pupo Laura

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

COVID-19 is a disease caused by an infectious outbreak of the SARS-CoV-2 virus. Today, the virus is widely spread throughout the world and declared by the World Health Organisation (WHO) as a pandemic. There are a broad range of clinical presentations of a SARS-CoV-2 viral infection varying from asymptomatic, sensation of a mild cold or flu to severe bilateral pneumonia and death. The mortality is the highest in the elderly and in people with a pre-existing condition such as cancer. In addition, it has already been shown that in patients with a severe COVID-19 infection the cytokine levels in the blood are very high, which can lead to organ failure. Since in cancer patients cytokine production is already increased by their disease and by treatment, this implies a higher susceptibility to develop severe COVID-19 when an exaggerated immune response to this virus produces even more cytokines ("cytokine storm"). The aim of this project is to be able to detect preventively when there is a risk of developing a "cytokine storm" so that potential therapy such as cytokine inhibitors can be used. To accomplish this, the response of the immune system to SARS-Cov2 infection will be mapped in this project. This will be done by performing immunological tests on blood samples from cancer patients and a healthcare workers the same oncology units who seropositive for the SARS-CoV-2 infection. Both blood samples from symptomatic and asymptomatic COVID-19 subjects will be examined immunologically. The immunological tests include immunoassays, flow cytometry and immunomethylomics. The collection of blood samples has already started at the end of March 2020 and the inclusion period is 3 months, so that the early phase, the peak phase and the foreseen decline of the pandemic are included. Cancer patients are asked to take additional blood samples during routine blood samples. A monthly blood sample is requested from the group of healthcare workers (4 samples per participant). First of all, the seropositive samples will be detected on the basis of a serological test. These results also provide insight into the proportion of infected high-risk patients in a hospital environment. On the basis of the immunological tests, the immune response will be compared between the symptomatic cancer patients and asymptomatic cancer patients and matched controlled healthcare workers. In this way, immunological risk factors for the development of severe COVID-19 can be identified and a new outbreak can be controlled in a scientifically responsible manner.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Huizing Manon
• Co-promoter: Peeters Marc
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Vulsteke Christof

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Every year, over 22.000 people are diagnosed with multiple myeloma (MM). In this type of cancer, malignant plasma cells uncontrollably accumulate within the bone marrow causing devastating and often fatal symptoms. Although several therapies exist today that can improve quality of life and survival rate, the cancer cells frequently become resistant thus rendering the disease incurable. In this context, a new and promising anti-cancer drug class, known as epigenetic (modifying) drugs, is currently being investigated. In this novel treatment approach, the focus lies on restoring the distorted gene expression in the mutated plasma cells that is both responsible for the malignant character of the disease and increased therapy resistance. This project aims to resolve the mechanism of action of a novel class of epigenetic bioactive phytochemicals such as Withaferin A, which is able to overcome therapy resistance in MM. Of particular interest, recent studies in my lab (PPES) suggest that the therapeutic potential of Withaferin A lies in its ability to epigenetically alter gene expression and even induce cancer cell death via a novel alternative oxidative stress and iron-dependent form of cell death named "ferroptosis". Finally, by combining multiple innovative pharmacological (pharmacology on a chip), proteomic and epigenomic strategies, we aim to identify epigenetic control mechanisms of Withaferin A dependent ferroptosis to overcome therapy resistance in multiple myeloma.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Logie Emilie

Research team(s)

Project type(s)

• Research Project

Abstract

How does 'rusting away' cancer work? Brothers Wim and Tom Vanden Berghe discovered an important new evolution in the field of cancer research: 'rusting away' therapy-resistant cancers. Our body is full of iron, and our cells are the building blocks. Cells can die if the iron they contain is not properly protected. This biological rusting process can also be used to eat away at cancer cells. Previous research has already focused on the effect of Withaferin A on chemotherapy-resistant cancer cells. An anti-inflammatory component found in the Indian winter cherry plant, it has the unique ability to attack cancer cells' built-in rust protection processes. With the help of nanotechnology Side effects are bypassed using nanotechnology, involving particles smaller than 100 nanometres. Just to put things in perspective: one nanometre is one millionth of a millimetre. The two brothers managed to envelop the plant-based component in a very tiny ball. When these minuscule 'rust bombs' are introduced into the bloodstream, they get lodged in tumours, because tumour blood vessels are often damaged and leak into the tumour tissue. This allows the rust process to start specifically inside tumours. From discovery to drug Wim Vanden Berghe, professor of epigenetics in the PPES research group at UAntwerp: "The discovery of Withaferin A in Indian winter cherry as a potential cure for resistant types of childhood cancer is incredibly important. The first results are promising, but there is still a long way to go before we can really start using this as a treatment. It requires additional research, and therefore additional resources.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

Obesity constitutes a major health problem, partly due to the increasing prevalence and secondly because of its associated morbidity. It is associated with increased amounts of adipose tissue as well as fat accumulation in non-adipose tissue such as liver and skeletal muscle. Accumulation of ectopic fat in the liver (non-alcoholic fatty liver disease, NAFLD) is a strong independent marker of dyslipidaemia and insulin resistance predisposing to the development of type 2 diabetes. Besides high caloric diet and lack of physical activity, pesticide exposure and endocrine disruptor pollutants are now also increasingly recognized as an "obesogenic" risk factor. Remarkably, recent genome- and epigenome wide associations studies highlight crosstalk of many obesity-associated genetic variants and environmental factors (diet, pesticides, exercise, alcohol consumption, smoking, drugs, medication) with DNA methylation changes at proximal promoters and enhancers. For example, we recently found a strong association between the paraoxonase 1 (PON1) p.Q192R genotype with pesticide exposure and adverse epigenetic (re)programming of endocrine pathways in obesity and high body fat content. PON members hydrolyze several pesticides, a number of exogenous and endogenous lactones and metabolizes toxic oxidized lipids of low density lipoproteins (LDL) and HDL. A decrease in PON1 expression promotes adverse lipid metabolism and is an important risk factor for cardiometabolic disease and has recently been found to be associated with childhood and adult obesity, liver steatosis and its more severe subtype of steatohepatitis. Differences in PON2 have been associated with obesity susceptibility in brown/white adipose tissue. Given the crucial role of PON members in protecting from adverse environmental exposure and from obesity, there is an urgent need for further molecular and clinical research on (epi)genetic PON(1-3) regulation mechanisms in this area. In this GOA, we want to further investigate associations of clinical characterized obesity phenotypes with PON(1-3) genetic variants/polymorphisms, associated epigenetic DNA methylation variation and PON(1-3) expression in samples (i.e. blood, serum, adipose or liver) of clinical patient cohorts diagnosed with obesity, NAFLD/NASH, in relation to adverse pesticide exposure or following therapeutic medical intervention (liraglutide or bariatric surgery). Functional investigation of genetic-epigenetic regulatory crosstalk of PON(1-3) expression in response to pollutant exposure or following medical interventions will be further investigated in relation to biochemical parameters of obesity/liver steatosis/adipocyte differentiation in cell models in vitro as well as in zebrafish in vivo. As such, a better understanding of variable PON(1-3) regulation of obesity-associated traits by adverse obesogenic pollutants or healthy intervention strategies may offer new perspectives to prevent obesity and/or promote cardiometabolic health.

Researcher(s)

• Promoter: Van Hul Wim
• Co-promoter: Francque Sven
• Co-promoter: Knapen Dries
• Co-promoter: Vanden Berghe Wim

Research team(s)

• Medical Genetics (MEDGEN)

Project type(s)

• Research Project

Abstract

During 2022, the main focus of project 1 will continue to be on the consolidation of the MSc pro-gramme on Biodiscovery launched in phase 1 and the enhancement of the capacities for de-mand-based research and stakeholder interactions. The MSc consolidation will consist of two main aspects: the development of an additional sustain-able scholarship program to allow more students to come back to face-to-face classes, and the inclusion of UTN as the fourth HEI for the MSc program. During the pandemic, less students regis-tered for the MSc program, and those who did attended classes online. Additionally, the program was run by ESPOL, EPN and UCuenca only. Thanks to the support from this program, UTN is now ready to offer the MSc program. A new MSc proposal including UTN as a host institution will be submitted to CES in 2022. The Network capacities for demand-based research and stakeholder interaction will continue with the consolidation of the Natural Products and the food safety consortia, in analogy to various valorisation initiatives organized by flanders.bio food/knowledge for growth programs (see com-ment workshop) . The selected valorisation managers will promote solid linkages with stakeholders for research and tech transfer activities. Additionally, the team will continue the network research on bioprospecting, and carry out exten-sion and outreach activities. Additional funding for the network will be pursued through local and international calls.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

This project focuses on the Kichwa community specifically in Tena city and different urbanization areas around Napo Province of Ecuador. We seek to examine the roles of the dairy nutrition in Kichwa mothers and their influences on their child during breastfeeding. This will be done by investigating the availability of food, the social-cultural environments and the crosstalk with nutritional-health factors in the oral saliva epigenome/microbiome of the mothers and children during breastfeeding in Tena. This proposal is crucial because (i) It identifies the cultural meaning of food selection process for this rural population (ii) Identifies the nutritional, health and environmental factors in mothers and children. (iii) It determines the influence of mother's diet in the children saliva epigenome/microbiome, (iv) it creates prevention programs and health-nutritional policy, (v) it promotes the use of traditional local foods and promotes new research in public health.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

Alzheimer's dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. Sofar, little is known about possible changes in protein kinase activity in the pathology of AD progression. Today, kinase inhibitors upstream or downstream of amyloid-β oligomer signaling hold promise as effective disease modifying strategies to attenuate or prevent AD progression. In this respect, there is an urgent need to investigate changes in protein kinase activity and the associated signalling pathways during AD progression and the potential of these kinases to be used as diagnostic biomarkers and drug targets. The low benefit of drugs which target one single kinase has enforced research towards multitargeting kinase inhibitor strategies in AD drug-discovery and to develop brain-permeable multitargeting protein kinase inhibitors with low cellular toxicity which attenuate protein kinase hyperactivity but do not block their physiological activity levels in normal cells. In preliminar studies In preliminar kinome activity profiling studies in cortex of different AD mice models (at the preplaque stage), we observed significant hyperactivation of Abl and Src (Fyn,Lck) kinase activities, related to neuroinflammation and neuronal cell survival/cell death. In the current proposal we want to apply phosphopeptidome profiling in the transgenic AD model APP23 to determine the kinome inhibitor profile of 2 promising AD modulator compounds withaferin A and saracatinib AZD0530 which have already shown to attenuate and/or reverse AD pathology: - we have purified and characterized a novel class of withaferin A related kinase inhibitors from Withania Somnifera (also known as "ashwagandha" in Ayurvedic medicine) which is able to reverse behavioral deficits, plaque pathology, accumulation of β-amyloid peptides (Aβ) and oligomers in the brains of middle-aged and old Alzheimer's disease transgenic mice. Briefly, these blood-brain permeable compounds promote cognition-memory and help to promote neurite outgrowth in cultured neurons and in rodents injected with Aβ . - In another study, the pharmacological src/fyn kinase inhibitor and cancer drug saracatinib AZD0530 was repurposed as a promising candidate for treatment of AD, since it was found to rescue established memory and synapse loss in a preclinical mouse model of Alzheimer disease upon kinase inhibition Moreover, AZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration in clinical trials. Recent reports support a role for kinase therapy as an effective disease modifying strategy in Alzheimer disease (AD). Peptide array based kinase activity (Pamchip) profiling is an innovative approach to reveal previously unknown kinase networks involved in AD pathology. It can lead to the discovery of novel diagnostic kinase biomarkers and druggable targets for treatment of AD disease . In this proposal we will identify kinase activity changes related to AD progression in a transgenic AD mouse model by Pamchip kinase activity profiling. Moreover, we will characterize the kinase inhibitor profile of Withaferin A and Saracatinib which are able to reverse AD pathology. This proposal wil contribute in development of a disease-modifying kinase therapy in AD which can revolutionize the care of millions of patients worldwide, with a major impact on rapidly escalating healthcare costs.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Glucocorticoids (GCs) have been employed as a conventional treatment option for various haematological diseases, including acute lymphoblastic leukaemia (ALL), chronic lymphoblastic leukaemia (CLL), multiple myeloma (MM), Hodgkin and non-Hodgkin lymphomas. These malignancies affecting children, young adults and the elderly, are all characterized by the abnormal growth of cells from the myeloid or lymphoid lineage. Despite the use of GCs as potential anti-cancer drugs, some tumours are not responsive to these drugs (primary resistance) and those which do respond develop resistance during therapy (acquired resistance). As such, the majority of patients relapse, develop resistance, or eventually might die from the disease within 5-10 years of initial diagnosis. The molecular basis of GC resistance is still poorly understood, although emerging evidence supports an important etiologic role for rewiring of cell death kinase signalling pathways. As such there is an urgent need to develop novel and better chemosensitising combination therapies with less adverse side effects. In addition, precise clinical staging and accurate identification of high-risk patients is important to determine GC therapy response, subsequent prognosis and allocate tailored (combination) treatment to each individual patient. We have identified Withaferin A (WA) as a top prioritized anti-cancer chemosensitizing compound for further (pre)clinical evaluation in GC resistant multiple myeloma and B- and T-cell leukemias. However, despite its promising chemosensitizing properties in vitro, preclinical validation in vivo is limited, due to lack of established mouse models for haematological malignancies. Moreover, commercial interest in preclinical studies with WA is lacking, since natural products can not be patented or since purification and/or full stereoselective synthesis of complex natural molecules can be problematic for translational biomedical applications. Based on our promising preliminar findings, chemosensitisation of GC resistant leukemia, lymphoma and myeloma cells by Withaferin A will be preclinically evaluated in different in vitro (cell models) and in vivo (genetically engineered mouse models and patient derived xenografts in immunedeficient animals) model systems. Furthermore, by using a novel innovative kinase peptide array platform, we will be able to establish a phosphopeptide fingerprint of kinome perturbations associated with GC resistance and/or chemosensitisation by WA in in vitro/in vivo samples as well as ex vivo patient samples. This phosphopeptide fingerprint will be applied as a diagnostic and/or predictive tool for personalized patient centered therapeutic applications (patient stratification) in treatment of poor prognosis GC resistant haematological malignancies.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project

Abstract

This project aims to advance the currently available sequencing technologies at the University of Antwerp (UA) by acquiring a third generation sequencing (3GS) platform. The flagship of the third generation, single-molecule longread sequencers, PacBio Sequel, harnesses the natural process of DNA replication and enables real-time observation of DNA synthesis. 3GS promises to open new avenues for sequencing-based research beyond the current state-of-the-art for this consortium, which consists of more than 14 UA research groups in various disciplines of medicine, biology and bioinformatics. Furthermore, several third parties have also committed to utilize this technology for their ongoing and future research studies. 3GS will be utilized by this consortium to (i) sequence prokaryotic and eukaryotic genomes, and difficult-to-sequence genome regions, (ii) identify new genes and mutations in various rare Mendelian disorders, (iii) identify epigenetic modifications to better understand biological processes like gene expression and host-pathogen interactions, (iv) precisely profile the human, murine, and environmental microbiome in disease and under various environmental stressors, and (v) develop novel preventive therapies for infection-prone disorders for better drug targeting. The analysis of the large amount of genomic and transcriptomic data generated by the various research groups will be coordinated by the UZA/UA bioinformatics group Biomina.

Researcher(s)

• Promoter: Malhotra Surbhi
• Co-promoter: Kumar-Singh Samir
• Co-promoter: Laukens Kris
• Co-promoter: Mortier Geert
• Co-promoter: Smet Annemieke
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van Rie Annelies

Research team(s)

• Laboratory of Medical Microbiology (LMM)

Project type(s)

• Research Project

Abstract

Every year, over 22.000 people are diagnosed with multiple myeloma (MM). In this type of cancer, malignant plasma cells uncontrollably accumulate within the bone marrow causing devastating and often fatal symptoms. Although several therapies exist today that can improve quality of life and survival rate, the cancer cells frequently become resistant thus rendering the disease incurable. In this context, a new and promising anti-cancer drug class, known as epigenetic (modifying) drugs, is currently being investigated. In this novel treatment approach, the focus lies on restoring the distorted gene expression in the mutated plasma cells that is both responsible for the malignant character of the disease and increased therapy resistance. This project aims to resolve the mechanism of action of a novel class of epigenetic bioactive phytochemicals such as Withaferin A, which is able to overcome therapy resistance in MM. Of particular interest, recent studies in my lab (PPES) suggest that the therapeutic potential of Withaferin A lies in its ability to epigenetically alter gene expression and even induce cancer cell death via a novel alternative oxidative stress and iron-dependent form of cell death named "ferroptosis". Finally, by combining multiple innovative pharmacological (pharmacology on a chip), proteomic and epigenomic strategies, we aim to identify epigenetic control mechanisms of Withaferin A dependent ferroptosis to overcome therapy resistance in multiple myeloma.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Logie Emilie

Research team(s)

Project type(s)

• Research Project

Abstract

This project combines the VLIR-UOS priorities of Public health with the ICT development and environmental policy and management in Cuba. Personalized medicine is one of the main goals of modern medicine in the search for longevity and welfare. Characterization of the Cuban population and the determination of geographic distribution of genotypes and epigenetic biomarkers among ethnic groups and the combination of bioinformatics and molecular tools will allow to improve cost-efficiency of lung cancer treatment in the country.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

The project aims to establish a multidisciplinary reference platform at CIDEM with improved capacity (infrastructure+ know-how/training) in natural drug research and development, which integrates preparation of plant extracts, extraction and purification, analytical and structural characterization, molecular pharmacological evaluation and design and evaluation of appropriate systems of drug delivery, which allows pharmaceutical and pharmacological studies of phytomedicinal and nutraceutical products according to international standards, to stimulate the use of natural products in the National System of Health (NSH) in Cuba.

Researcher(s)

• Promoter: Apers Sandra
• Promoter: Pieters Luc
• Co-promoter: Kiekens Filip
• Co-promoter: Pieters Luc
• Co-promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Aging has profound effects on many cellular processes that predispose to neurodegeneration, impairment in cognitive function, as well as changes in brain functional connectivity networks (e.g. default mode network) and synaptic alterations. However, the key mechanisms orchestrating brain aging remain largely unknown. More and more findings in rodents and humans have established that inflammatory processes in the hypothalamus can contribute to neurodegeneration upon aging via reproductive (HPG) axis. However, the exact mechanisms by which (i) Inflammatory signalling in the hypothalamus contributes to the occurrence of age-related functional connectivity and synaptic alterations, and (ii) hypothalamic HPG signalling modulates age-related neurodegeneration and cognitive changes are not well understood and need further investigation. The main goals of this project are to investigate: (i) how deregulation of the HPG axis impacts brain networks that display aging decline, (ii) how hypothalamic inflammation is steering deregulation of HPG axis in healthy aging, accelerated aging and pathological aging, and (iii) how hypothalamic inflammatory responses become activated upon healthy, accelerated and pathological aging, with specific focus on cellular, connectional architecture of functional networks. This project will contribute new information that will greatly increase our understanding about underlying mechanisms of hypothalamus-driven systematic aging of the brain.

Researcher(s)

• Promoter: Van Der Linden Annemie
• Co-promoter: Ponsaerts Peter
• Co-promoter: Vanden Berghe Wim
• Fellow: Kara Firat

Research team(s)

• Bio-Imaging lab

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the Hercules Foundation. UA provides the Hercules Foundation research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Kooy Frank
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Van Ostade Xaveer

Research team(s)

Project type(s)

• Research Project

Abstract

In this project we want to use novel and established epigenetic inhibitor/activator molecules to investigate how epigenetic enzymes modulate GC induced cell death pathways in leukemia. Secondly, we want to understand how specific GC ligands can modulate cell therapy sensitivity/response by epigenetic reprogramming of cell survival/death pathways.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Proposed by the University, the Francqui Foundation each year awards two Francqui Chairs at the UAntwerp. These are intended to enable the invitation of a professor from another Belgian University or from abroad for a series of ten lessons. The Francqui Foundation pays the fee for these ten lessons directly to the holder of a Francqui Chair.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Drug resistance is well known in chronic lymphocytic leukemia therapy, where multidrug-resistant lymphoid cancers defy the most powerful chemotherapeutics available. In this respect, there is a renewed interest in multifocal anti-cancer compounds which simultaneously inhibit multiple signal transduction/survival pathways. We have identified Withaferin A (WA) as a very effective anti-cancer compound, which chemosensitizes various therapy resistant cancers, by binding molecules from different survival pathways. Hence, there is an essential need for investigations that can 1) provide a global view of cellular targets of WA and 2) select from this pool those interactions that are responsible for the anticancer effect. Such studies can lead to faster optimization of WA treatment, understanding of off-target side effects and the ability to minimize possible toxicities early on in the process. In this proposal, WA-specific binding proteins responsible for anti-cancer effects of WA will be determined in the JVM2 CLL cell model or primary CD19+ enriched PBMC samples from CLL patients and healthy donors by applying affinity based SILAC and iTRAQ proteomic methods using biotinylated WA (active compound) or biotinylated WN (inactive WA analogue). The established WA-specific protein network will be combined with gene expression array datasets, by applying systems biology bioinformatic approaches (IPA, Nextbio, GO, KEGG, STRING, GProfile, Cytoscape). Key target proteins of WA, involved in its anti-cancer effects will be validated in affinity pull down and silencing studies in JVM2 CLLs, and CD19+ enriched PBMC samples from healthy donors or CLL patients.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Van Ostade Xaveer

Research team(s)

Project type(s)

• Research Project

Abstract

Rapid evolution in analytical technologies including next generation sequencing and mass spectrometry recently boosted the systematic analysis of molecular layers such as the transcriptome, epigenome and proteome. Datasets of enormous size and diversity are now routinely generated in Systems Biology research projects. The advances in the acquisition of these diverse data are followed by the development of new bioinformatics approaches, typically each dedicated to the analysis and interpretation of a specific data type. The separate analysis of each data type does not suffice anymore to satisfy the need for a multi-perspective understanding of biological processes and diseases, which is imperative in modern Systems Biology. Different 'omics datasets should not only be analysed separately, but also be integrated and compared, in order to reveal patterns that encompass multiple 'omics layers. This is an underexplored research area in the bioinformatics field. At the PPES lab of Proteomics & Epigenetic Signaling, parallel transcriptomic (Illumina Array, miRNA QPCR array), epigenomic (MBD2seq, Illumina CpG array) and chemoproteomic (SILAC/iTrAQ) assays have been performed on different cancer cell types treated with the very potent tumor selective anticancer drug Withaferin A, to get a comprehensive view of cellular networks targeted during chemosensitisation. By an integrated analysis of our available datasets, we want to identify key proteins/nodes/pathways responsible for the potent chemosensitizing anti-cancer effects of Withaferin A. In this doctoral project, novel bioinformatic methodologies will be developed and studied which enable the integrative analysis of these three different quantitative omics data types (transcriptome, epigenome and proteome) with high relevance for research ongoing in and outside the University.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Laukens Kris
• Fellow: Naulaerts Stefan

Research team(s)

Project type(s)

• Research Project

Abstract

To reduce the cancer mortality in Cuba, the development of novel cost-effective cancer therapies based on phytomedicinal products from indigenous natural sources, is one of the priorities of the Cuban Ministry of Health. Previous collaborative studies have already identified pure mangiferin as a major bioactive compound in Mangifera indica L. extract (Vimang), with potent anti-cancer properties in vitro/in vivo. Cuban researchers will now be trained in molecular biological approaches in cancer research, as well as in mangiferin pharmacology, pharmacognosy and pharmacodynamics in order to conduct preclinical cancer studies in vivo in laboratory animals, Because of the high economical value of mangotrees (Mangifera indica L.) in tropical fruit industry in Cuba, agronomic and metabolic studies are also conducted to optimize sustainable, ecological cost-effective production methods of mangiferin from the bark or the leaves of the mangotree, which do not decrease mango fruit yield of the mangotree. Altogether, this project will assist Cuba to train experts in cancer studies and to include mangiferin as a novel sustainable cost-effective anti-cancer compound from an indigenous natural source, for further development into anti-cancer therapies in Cuba.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

This 'proof-of-concept' research is focussed on the development of innovative long-lasting and selective glucocorticoid receptor agonists for the topical treatment of skin inflammation diseases such as atopic dermatitis and psoriasis.

Researcher(s)

• Promoter: Augustyns Koen
• Co-promoter: Joossens Jurgen
• Co-promoter: Lambert Julien
• Co-promoter: Maes Louis
• Co-promoter: Sobott Frank
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van Der Veken Pieter

Research team(s)

• Medicinal Chemistry (UAMC)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Preparation of a project on 'Molecular Characterization and valorization of Cuban natural products in Particular Vimang glucoxylsanthone mangiferin and Its Naturally, for therapeutic applications against Cancer and inflammation'.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Therapy resistant metastatic tumors with a bad prognosis typically demonstrate a strong inflammatory gene expression profile and severe hypoxic and hypoglycemic growth conditions.In macrophages and different tumor cell types, we want to characterize combined effects of hypoxia and inflammation on NFkB-, Stat3- and HIF-dependent signaling pathways resulting in epigenetic programming of cancer cells by PML, Jmjd3, LSD1 and SIRT chromatin-associated factors

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Van Ostade Xaveer

Research team(s)

Project type(s)

• Research Project

Abstract

Short exposure to nutrients, toxines, endocrine disruptors, hormones, famine or stress, can have longlasting consequences by epigenetic mechanisms (chromatin code, DNA methylation, noncoding RNAs) which affect the interpretation and expression of the genetic DNA blueprint. As such chronic inflammation is epigenetically recorded in the human genome and increase incidence and progression of various diseases, including metabolic disease, autoimmune disease, cancer, neurodegeneration, cardiovascular disease and ageing. This research will explore how diet and environmental factors interfere with epigenetic regulation of immune homeostasis in health and disease.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Fellow: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Short exposure to nutrients, toxines, endocrine disruptors, hormones, famine or stress, can have longlasting consequences by epigenetic mechanisms (chromatin code, DNA methylation, noncoding RNAs) which affect the interpretation and expression of the genetic DNA blueprint. As such chronic inflammation is epigenetically recorded in the human genome and increase incidence and progression of various diseases, including metabolic disease, autoimmune disease, cancer, neurodegeneration, cardiovascular disease and ageing. This research will explore how diet and environmental factors interfere with epigenetic regulation of immune homeostasis in health and disease.

Researcher(s)

• Promoter: Vanden Berghe Wim

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Dewilde Sylvia
• Promoter: Moens Luc
• Promoter: Vanden Berghe Wim
• Promoter: Van Ostade Xaveer

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project type(s)

• Research Project