ERC FUNDED PROJECTS

The goal of this project is to develop inexpensive, high-throughput technology to screen the thus far unexplored metabolic interactions between environmental and household chemicals and clinically relevant drugs. The main influential focus will be on human phase I metabolism (redox reactions) of common toxicants like agrochemicals and plasticizers. On the basis of their structural resemblance to pharmaceuticals and endogenous compounds, many of these chemicals are suspected to have critical effects on cytochrome P450 metabolism which is the main detoxification route of pharmaceuticals in man. However, with the current analytical instrumentation, screening of such large chemical pool would take several years, and new chemicals would be introduced faster than the old ones are screened. Thus, the main technological goal of this project is to develop novel, practically zero-cost analytical instruments that enable characterization of a compound’s metabolic profile at very high speed (<1 min/sample). This goal is achieved through miniaturization and high degree of integration of analytical instrumentation by microfabrication means, an approach often called lab(oratory)-on-a-chip. The microfabricated arrays are envisioned to incorporate all analytical key functions required (i.e., sample pretreatment, metabolic reaction, separation of the reaction products, detection) on a single chip. Thanks to the reduced dimensions, the amount of chemical waste and consumption of expensive reagents are significantly reduced. In this project, several different microfabrication techniques, from delicate cleanroom processes to extremely simple printing techniques, will be exploited to produce smart microfluidic designs and multifunctional surfaces. Towards the end of the project, more focus will be put on “printable microfluidics” which provides a truly low-cost approach for fabrication of highly customized microfluidic assays. Numerical modelling is also an integral part of the work.

1 499 668 €

Start date: 2013-05-01, End date: 2019-02-28

In recent years, genome-wide association studies (GWAS) have discovered hundreds of single nucleotide polymorphisms (SNPs) which are significantly associated with coronary artery disease (CAD). However, the SNPs identified by GWAS explain typically only small portion of the trait heritability and vast majority of variants do not have known biological roles. This is explained by variants lying within noncoding regions such as in cell type specific enhancers and additionally ‘the lead SNP’ identified in GWAS may not be the ‘the causal SNP’ but only linked with a trait associated SNP. Therefore, a major priority for understanding disease mechanisms is to understand at the molecular level the function of each CAD loci. In this study we aim to bring the functional characterization of SNPs associated with CAD risk to date by focusing our search for causal SNPs to enhancers of disease relevant cell types, namely endothelial cells, macrophages and smooth muscle cells of the vessel wall, hepatocytes and adipocytes. By combination of massively parallel enhancer activity measurements, collection of novel eQTL data throughout cell types under disease relevant stimuli, identification of the target genes in physical interaction with the candidate enhancers and establishment of correlative relationships between enhancer activity and gene expression we hope to identify causal enhancer variants and link them with target genes to obtain a more complete picture of the gene regulatory events driving disease progression and the genetic basis of CAD. Linking these findings with our deep phenotypic data for cardiovascular risk factors, gene expression and metabolomics has the potential to improve risk prediction, biomarker identification and treatment selection in clinical practice. Ultimately, this research strives for fundamental discoveries and breakthrough that advance our knowledge of CAD and provides pioneering steps towards taking the growing array of GWAS for translatable results.

1 498 647 €

Start date: 2019-01-01, End date: 2023-12-31

Conventional cancer therapies suffer from poor efficacy owing to the lack of efficient delivery systems and to the inherent tumor heterogeneity that requires multi-modal approach to abrogate cancer progression. Nanotechnology holds promise to address these drawbacks, as the use of (bio)nanomaterials for diagnostics and therapy has been gaining momentum over the last years. The main goal of this project is to develop a novel and facile platform capable of profiling both the therapy outcome and heterogeneity in cancer, by using bioresponsive nanohydrogels for the delivery of logic multicolor synthetic gene circuits. These logic synthetic gene circuits will be designed as a biobarcode of multicolor RNA circuits embedded in hybrid nanoparticles and doped in hydrogels for local therapy in breast cancer in vivo. Using cell-type specific promoters, the multicolor miRNA circuits will be expressed specifically to each type of the cells of the tumor microenvironment. Subsequently, this will permit to evaluate the therapeutic efficacy in a cell-by-cell basis and to profile the tumor heterogeneity across different breast cancer types. In order to potentiate the translation of this ground-breaking platform into clinics and precision medicine, novel de-regulated miRNA targets will be identified based on screens performed in breast cancer patient-derived tumors that better reflect the heterogeneous tumor microenvironment in a patient-by-patient basis. In sum, the material platforms developed herein and newly identified biological targets can be harnessed to design effective cancer treatments that go beyond breast cancer. The project is highly versatile and multidisciplinary and this system can be easily adapted to target any cancer cell type and molecular mechanisms and translated to clinical testing.

1 435 312 €

Start date: 2020-02-01, End date: 2025-01-31

The considerable variability within tissue microenvironments as well as the multiclonality of cancers leads to intratumoral heterogeneity. This increases the probablility of cellular states that promote resistance to therapy and eventually lead to reconstitution of the tumor by treatment-resistant cancer cells, which in some cases have properties of normal tissue stem cells. Wnt signals are important in the maintenance of stem cells in various epithelial tissues, including in lung development and regeneration. We hypothesized that Wnt signals contribute to tumor heterogeneity in genetically engineered KrasG12D; Tp53Δ/Δ (”KP”) mouse lung adenocarcinomas (LUAD). We observed that a subpopulation of LUAD cells exhibited high Wnt reporter activity and had increased tumor forming ability, which could be suppressed by silencing of Wnt signaling pathway components or by small molecule Wnt inhibitors in vitro and in vivo. KP LUAD cells show hierarchical features with two distinct populations, one with increased Wnt reporter activity and another forming a niche that provides the Wnt signal. Lineage-tracing experiments in the autochthonous KP tumors demonstrated that Wnt responder cells have increased tumor propagation ability in vivo. Strikingly, selective ablation of the Wnt responder cells resulted in tumor stasis. CRISPR-based targeting or small molecules targeting Wnt signaling reduced tumor growth and prolonged survival in the autochthonous KP mouse lung cancer model. These results indicate that maintenance of heterogeneity within tumors may be advantageous for the tumor cell population collectively. We propose to elucidate the molecular and cellullar mechanisms that control stem-like and niche cell phenotypes using a combination of novel lentiviral vectors and genetically modified mice in the context of the KP LUAD model. These efforts may lead to novel therapeutic concepts in human lung cancer.

1 972 905 €

Start date: 2017-07-01, End date: 2022-06-30