ERC FUNDED PROJECTS

"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

Annually 1.2 million new cases of colorectal cancer (CRC) are seen worldwide and over 50% of patients die of the disease making it a leading cause of cancer-related mortality. A crucial contributing factor to these disappointing figures is that CRC is a heterogeneous disease and tumours differ extensively in the clinical presentation and response to therapy. Recent unsupervised classification studies highlight that only a proportion of this heterogeneity can be explained by the variation in commonly found (epi-)genetic aberrations. Hence the origins of CRC heterogeneity remain poorly understood. The central hypothesis of this research project is that the cell of origin contributes to the phenotype and functional properties of the pre-malignant clone and the resulting malignancy. To study this concept I will generate cell of origin- and mutation-specific molecular profiles of oncogenic clones and relate those to human CRC samples. Furthermore, I will quantitatively investigate how mutations and the cell of origin act in concert to determine the functional characteristics of the pre-malignant clone that ultimately develops into an invasive intestinal tumour. These studies are paralleled by the investigation of stem cell dynamics within established human CRCs by means of a novel marker independent lineage tracing strategy in combination with mathematical analysis techniques. This will provide critical and quantitative information on the relevance of the cancer stem cell concept in CRC and on the degree of inter-tumour variation with respect to the frequency and functional features of stem-like cells within individual CRCs and molecular subtypes of the disease. I am convinced that a better and quantitative understanding of the dynamical properties of stem cells during tumour development and within established CRCs will be pivotal for an improved classification, prevention and treatment of CRC.

1 499 875 €

Start date: 2015-04-01, End date: 2021-03-31

Bone marrow (BM) fibrosis is the continuous replacement of blood forming cells in the bone marrow by scar tissue, ultimately leading to failure of the body to produce blood cells. Primary myelofibrosis (PMF), an incurable blood cancer, is the prototypic example of the step-wise development of BM fibrosis. The specific mechanisms that cause BM fibrosis are not understood, in particular as the cells driving fibrosis have remained obscure. My recent findings demonstrate that Gli1+ cells are fibrosis-driving cells in PMF, that their frequency correlates with fibrosis severity in patients, and that their ablation ameliorates BM fibrosis. These results indicate that Gli1+ cells are the primary effector cells in BM fibrosis and that they represent a highly attractive therapeutic target. This puts me in a unique position to vastly expand our knowledge of the BM fibrosis pathogenesis, improve diagnostics, and discover new therapeutic strategies for this fatal disease. I will do this by: 1) dissecting the molecular and cellular mechanisms of the fibrotic transformation, 2) defining the stepwise disease evolution by genetic fate tracing and analysis of the previously unknown critical effector cells of BM fibrosis , 3) understanding early forms of BM fibrosis for improved diagnostics in patients, all with the ultimate aim to identify novel therapeutic targets to directly block the cellular and molecular changes occuring in BM fibrosis. I will apply state-of-the-art techniques, including genetic fate tracing experiments, conditional genetic knockout mouse models, tissue engineering of the bone marrow niche and in vivo and in vitro CRISPR/Cas9 gene editing, to unravel the complex molecular and cellular interaction between fibrosis-causing cells and the malignant hematopoietic cells. I will translate these findings into patient samples with the aim to improve the early diagnosis of the disease and to ultimately develop novel targeted therapies with curative intentions.

1 498 544 €

Start date: 2018-01-01, End date: 2022-12-31