ERC FUNDED PROJECTS

In the last forty years, researchers in the Field of Migration and Ethnic Studies looked at the integration of migrants and their descendants. Concepts, methodological tools and theoretical frameworks have been developed to measure and predict integration outcomes both across different ethnic groups and in comparison with people of native descent. But are we also looking into the actual integration of the receiving group of native ‘white’ descent in city contexts where they have become a numerical minority themselves? In cities like Amsterdam, now only one in three youngsters under age fifteen is of native descent. This situation, referred to as a majority-minority context, is a new phenomenon in Western Europe and it presents itself as one of the most important societal and psychological transformations of our time. I argue that the field of migration and ethnic studies is stagnating because of the one-sided focus on migrants and their children. This is even more urgent given the increased ant-immigrant vote. These pressing scientific and societal reasons pushed me to develop the project BAM (Becoming A Minority). The project will be executed in three harbor cities, Rotterdam, Antwerp and Malmö, and three service sector cities, Amsterdam, Frankfurt and Vienna. BAM consists of 5 subprojects: (1) A meta-analysis of secondary data on people of native ‘white’ descent in the six research sites; (2) A newly developed survey for the target group; (3) An analysis of critical circumstances of encounter that trigger either positive or rather negative responses to increased ethnic diversity (4) Experimental diversity labs to test under which circumstances people will change their attitudes or their actions towards increased ethnic diversity; (5) The formulation of a new theory of integration that includes the changed position of the group of native ‘white’ descent as an important actor.

2 499 714 €

Start date: 2017-11-01, End date: 2022-10-31

The human genome carries genetic information in two distinct forms: Transcribed genes and regulatory DNA elements (rDEs). rDEs control the magnitude and pattern of gene expression, and are indispensable for organismal development and cellular homeostasis. Nevertheless, while large-scale functional genetic screens greatly advanced our knowledge in studying mammalian genes, such tools to study rDEs were lacking, impeding scientific progress. Interestingly, recent advance in genome editing technologies has not only expanded the available screening toolbox to examine genes, but also opened up novel opportunities in studying rDEs. We distinguish two types of rDEs: Transcriptional rDEs that recruit transcription factors to enhancers, and structural rDEs that maintain chromatin 3D structure to insulate transcriptional activities, a feature postulated to be essential for gene expression regulation by enhancers. Recently, we developed a CRISPR strategy to target enhancers. We showed its scalability and effectivity in identifying potential oncogenic and tumour-suppressive enhancers. Here, we will exploit this line of research and develop novel strategies to target structural rDEs (e.g. insulators). By setting up functional genetic screens, we will identify key players in cell proliferation, differentiation, and survival, which are related to cancer development, metastasis induction, and acquired therapy resistance. We will validate key insulators and decipher underlying mechanisms of action that control phenotypes. In a parallel approach, we will analyse whole genome sequencing datasets of cancer to identify and characterize genetic aberrations occurring in the identified regions. Altogether, the outlined research plan forms a natural extension of our successful functional approaches to study gene regulation. Our results will setup the foundation to better understand principles of chromatin architecture in gene expression regulation in development and cancer.

2 497 000 €

Start date: 2019-09-01, End date: 2024-08-31

"Heart failure is a serious clinical disorder that represents the primary cause of hospitalization and death in Europe and the United States. There is a dire need for new paradigms and therapeutic approaches for treatment of this devastating disease. The heart responds to mechanical load and various extracellular stimuli by hypertrophic growth and sustained pathological hypertrophy is a major clinical predictor of heart failure. A variety of stress-responsive signaling pathways promote cardiac hypertrophy, but the precise mechanisms that link these pathways to cardiac disease are only beginning to be unveiled. Signal transduction is traditionally concentrated on the protein coding part of the genome, but it is now appreciated that the protein coding part of the genome only constitutes 1.5% of the genome. RNA based mechanisms may provide a more complete understanding of the fundamentals of cellular signaling. As a proof-of-principle, we focus on a principal hypertrophic signaling cascade, cardiac calcineurin/NFAT signaling. Here we will establish that microRNAs are intimately interwoven with this signaling cascade, influence signaling strength by unexpected upstream mechanisms. Secondly, we will firmly establish that microRNA target genes critically contribute to genesis of heart failure. Third, the surprising stability of circulating microRNAs has opened the possibility to develop the next generation of biomarkers and provide unexpected mechanisms how genetic information is transported between cells in multicellular organs and fascilitate inter-cellular communication. Finally, microRNA-based therapeutic silencing is remarkably powerful and offers opportunities to specifically intervene in pathological signaling as the next generation heart failure therapeutics. CALMIRS aims to mine the wealth of these RNA mechanisms to enable the development of next generation RNA based signal transduction biology, with surprising new diagnostic and therapeutic opportunities."

1 499 528 €

Start date: 2013-02-01, End date: 2018-01-31

Introduction: Current anti-cancer treatments are often inefficient, while many patients initially benefit from anti-cancer drugs eventually experience relapse of resistant tumors throughout the body. Current clinical strategies mainly aim at inducing tumor cell death, but this induction may have unintentional and unwanted side effects on surviving tumor cells. Preliminary data: We show that after chemotherapy-induced initial regression, PyMT mammary tumors reappear. During regression, we observe an increased number of cells that have undergone epithelial-mesenchymal transition (EMT) and become migratory. We show that migration can be induced upon uptake of extracellular vesicles (e.g. apoptotic bodies). Our findings suggest that EMT is induced upon chemotherapy, through e.g. EV uptake, potentially leading to migration and growth of surviving cells. Hypothesis and main aim: Based on preliminary data, we hypothesize that tumor cell death induces migration and growth of the surviving tumor cells. We aim to identify the key cell types and mechanisms that mediate this effect, and establish whether interference with these cells and mechanisms can reduce recurrence of tumors after chemotherapy. Approach: We have developed unique intravital imaging tools and genetically engineered fluorescent mice to visualize and characterize if and how dying tumor cells can affect surrounding surviving tumor and stromal cells. We will test whether dying tumor cells can influence the growth, migration, dissemination and metastasis of surviving tumor cells directly or indirectly through stromal cells. We will identify potential targets to block the influence of the dying tumor cells, and test whether this blockade inhibits the unintended side-effects of tumor cell death. Conclusion: With the studies proposed in this grant, we will gain fundamental insights on how induction of tumor cell death, the universal aim of therapy, could play a role in growth and spread of surviving tumor cells.

2 000 000 €

Start date: 2015-09-01, End date: 2020-08-31