ERC FUNDED PROJECTS

"Translational research aims at applying mechanistic understanding in the development of "precision medicine", which depends on precise diagnostic tools and therapeutic approaches. Cancer therapy is experiencing a switch from non-specific, cytotoxic agents towards molecularly targeted and rationally designed compounds with the promise of greater efficacy and fewer side effects. The two cell-cycle kinases CDK4 and CDK6 normally facilitate cell-cycle progression but are abnormally activated in certain cancers. CDK6 is up-regulated in hematopoietic malignancies, where it is the predominant cell-cycle kinase. The importance of CDK4/6 for tumor development is underscored by the fact that the US FDA selected inhibitors of the kinase activity of CDK4/6 as "breakthrough of the year 2013". Our recent findings suggest that the effects of the inhibitors may be limited as CDK6 is not only involved in cell-cycle progression: ground-breaking research in my group and others has shown that CDK6 is involved in regulation of transcription in a kinase-independent manner thereby driving the proliferation of leukemic stem cells and tumor formation. We have now identified mutations in CDK6 that convert it from a tumor promoter into a tumor suppressor. This unexpected outcome is accompanied by a distinct transcriptional profile. Separating the tumor-promoting from the tumor suppressive functions may open a novel therapeutic avenue for drug development. We aim at understanding which domains and residues of CDK6 are involved in rewiring the transcriptional landscape to pave the way for sophisticated inhibitors. The idea of turning a cancer cell's own most potent weapon against itself is novel and would represent a new paradigm for drug design. Finally, the understanding of CDK6 functions in tumor promotion and maintenance will also result in better patient stratification and improved treatment decisions for a broad spectrum of cancer types."

2 497 520 €

Start date: 2016-09-01, End date: 2021-08-31

Immunotherapy with checkpoints blockers is transforming the treatment of advanced cancers. Colorectal cancer (CRC), a cancer with 1.4 million new cases diagnosed annually worldwide, is refractory to immunotherapy (with the exception of a minority of tumors with microsatellite instability). This is somehow paradoxical as CRC is a cancer for which we have shown that it is under immunological control and that tumor infiltrating lymphocytes represent a strong independent predictor of survival. Thus, there is an urgent need to broaden the clinical benefits of immune checkpoint blockers to CRC by combining agents with synergistic mechanisms of action. An attractive approach to sensitize tumors to immunotherapy is to harness immunogenic effects induced by approved conventional or targeted agents. Here I propose a new paradigm to identify molecular determinants of resistance to immunotherapy and develop personalized in silico and in vitro models for predicting response to combination therapy in CRC. The EPIC concept is based on three pillars: 1) emphasis on antitumor T cell activity; 2) systematic interrogation of tumor-immune cell interactions using data-driven modeling and knowledge-based mechanistic modeling, and 3) generation of key quantitative data to train and validate algorithms using perturbation experiments with patient-derived tumor organoids and cutting-edge technologies for multidimensional profiling. We will investigate three immunomodulatory processes: 1) immunostimulatory effects of chemotherapeutics, 2) rewiring of signaling networks induced by targeted drugs and their interference with immunity, and 3) metabolic reprogramming of T cells to enhance antitumor immunity. The anticipated outcome of EPIC is a precision immuno-oncology platform that integrates tumor organoids with high-throughput and high-content data for testing drug combinations, and machine learning for making therapeutic recommendations for individual patients.

2 460 500 €

Start date: 2018-10-01, End date: 2023-09-30

How does information processing in neural circuits generate behaviour? Answering this question requires identifying each of the distinct neuronal types that contributes to a behaviour, defining their anatomy and connectivity, and establishing causal relationships between their activity, the activity of other neurons in the circuit, and the behaviour. Here, I propose such an analysis of the neural circuits that guide Drosophila mating behaviours. The distinct mating behaviours of males and females are genetically pre-programmed, yet can also be modified by experience. The set of ~2000 neurons that express the fru gene have been intimately linked to both male and female mating behaviours. This set of neurons includes specific sensory, central, and motor neurons, at least some of which are directly connected. Male-specific fruM isoforms configure this circuit developmentally for male rather than female behaviour. In females, mating triggers a biochemical cascade that reconfigures the circuit for post-mating rather than virgin female behaviour. We estimate that there are ~100 distinct classes of fru neuron. Using genetic and optical tools, we aim to identify each distinct class of fru neuron and to define its anatomy and connectivity. By silencing or activating specific neurons, or changing their genetic sex, we will assess their contributions to male and female behaviours, and how these perturbations impinge on activity patterns in other fru neurons. We also aim to define how a specific experience can modify the physiological properties of these circuits, and how these changes in turn modulate mating behaviour. These studies will define the operating principles of these neural circuits, contributing to a molecules-to-systems explanation of Drosophila s mating behaviours.

2 492 164 €

Start date: 2009-07-01, End date: 2013-09-30

"Because of its biological complexity, cancer is still poorly understood. Chronic inflammation has been shown, both experimentally and epidemiologically, to be a predisposition to, and also an inseparable aspect of clinically prevalent cancer entities. Therefore, a detailed understanding of both tumour and immune cell functions in cancer progression is a prerequisite for more successful therapeutic startegies. My team was the first to reveal the lymphocyte-intrinsic PKC/NR2F6 axis as an essential signalling node at the crossroads between inflammation and cancer. It is the mission of this project to identify molecular signatures that influence the risk of developing tumours employing established research tools and state-of-the-art genetic, biochemical, proteomic and transcriptomic as well as large scale CRISPR/Cas9 perturbation screening-based functional genomic technologies. Defining this as yet poorly elucidated effector pathway with its profoundly relevant role would enable development of preventive and immune-therapeutic strategies against NSCLC lung cancer and potentially also against other entities. Our three-pronged approach to achieve this goal is to: (i) delineate biological and clinical properties of the immunological PKC/NR2F6 network, (ii) validate NR2F6 as an immune-oncology combination target needed to overcome limitations to ""first generation anti-PD-1 checkpoint inhibitors"" rendering T cells capable of rejecting tumours and their metastases at distal organs and (iii) exploit human combinatorial T cell therapy concepts for prevention of immune-related adverse events as well as of tumour recurrence by reducing opportunities for the tumour to develop resistance in the clinic. Insight into the functions of NR2F6 pathway and involved mechanisms is a prerequisite for understanding how the microenvironment at the tumour site either supports tumour growth and spread or prevents tumour initiation and progression, the latter by host-protective cancer immunity."

2 484 325 €

Start date: 2018-10-01, End date: 2023-09-30

Most of our knowledge on human development and physiology is derived from experiments done in animal models. While these experiments have led to a comprehensive understanding of the principles of neurogenesis, animal models often fall short of modelling many of the most common neurological disorders. Recent experiments have revealed characteristic striking differences in brain development between rodents and primates and may provide an explanation for this problem. The goal of this proposal is to use three dimensional organoid cultures derived from pluripotent human stem cells to reveal the human specific aspects of brain development and to analyse neurological disease mechanisms directly in human tissue. We have recently developed a 3D culture method allowing us to recapitulate human brain development during the first trimester of embryogenesis. Using this method, we will define the human specific brain patterning events in order to develop a culture system that can recapitulate essentially any part of the brain. Using a unique combination of cell type specific markers and mutagenic viruses, we will define the transcriptional networks defining specific neuronal subtypes. This will allow us to perform loss-of function genetics in human tissue to define transcription factors necessary for development of individual neuronal subtypes on a genome-wide level. Finally, we will apply the genome wide screening technology to human neurological disorders like microcephaly or schizophrenia to identify factors that can rescue disease phenotypes. This research proposal will provide fundamental insights into the cellular and molecular mechanisms specifying various neuronal subclasses in the human brain and establish technology that can be applied to a variety of cell types and brain regions. The proposed experiments have the potential to yield fundamental insights into human neurological disease mechanisms that can currently not be derived from animal models.

2 800 000 €

Start date: 2017-01-01, End date: 2021-12-31

"Nitrification is a central component of the Earth’s biogeochemical nitrogen cycle. This process is driven by two groups of microorganisms, which oxidize ammonia via nitrite to nitrate. Their activities are of major ecological and economic importance and affect global warming, agriculture, wastewater treatment, and eutrophication. Despite the importance of nitrification for the health of our planet, there are surprisingly large gaps in our fundamental understanding of the microbiology of this process. Nitrifiers are difficult to isolate and thus most of our current knowledge stems from a few cultured model organisms that are hardly representative of the microbes driving nitrification in the environment. The overarching objective of NITRICARE is to close some of these knowledge gaps and obtain a comprehensive basic understanding of the identity, evolution, metabolism and ecological importance of those bacteria and archaea that actually catalyze nitrification in nature. For this purpose innovative single cell technologies like Raman-microspectroscopy, NanoSIMS and single cell genomics will be combined in novel ways and a Raman microfluidic device for high-throughput cell sorting will be developed. Application of these approaches will reveal the evolutionary history and metabolic versatility of uncultured ammonia oxidizing archaea and will provide important insights into their population structure. Furthermore, the proposed experiments will allow us to efficiently search for unknown nitrifiers, evaluate their ecological importance and test the hypothesis that organisms catalyzing both steps of nitrification may exist. For non-model nitrifiers we will develop a unique genetic approach to reveal the genetic basis of key metabolic features. Together, the genomic, metabolic, ecophysiological and genetic data will provide unprecedented insights into the biology of nitrifying microbes and open new conceptual horizons for the study of microbes in their natural environments."

2 499 107 €

Start date: 2012-05-01, End date: 2017-04-30

Ligand-gated and voltage-gated channels are key molecules in transforming chemical signals into electrical ones and electrical signals into chemical ones, respectively. At excitatory synaptic connections in the brain, activation of AMPA- and NMDA-type glutamate receptors elicits inward currents at the postsynaptic sites, and activation of voltage-gated calcium channels triggers vesicle release of glutamate in the presynaptic sites. Plastic changes in their number, location and property can lead to potentiation or depression of synaptic efficacy, alteration in time course, and coupling to effectors at both postsynaptic and presynaptic sites. These channels are all composed of distinct subunits and their compositions affect channel properties, trafficking to the synaptic sites, and interaction with associated molecules, creating a large diversity of synaptic functions. Although channels with different subunit compositions have been investigated using biochemical and electrophysiological detection methods, very little is known about single channel subunit composition in situ because of the lack of high resolution methods for analysis of protein complex in intact tissues. In this project, I will develop novel technologies to visualize subunit composition at the single channel level in individual synapses by electron microscopy, combining new EM tags, freeze-fracture replica labelling, and electron tomography. Synaptic plasticity will be induced by optogenetic stimulation of identified neurons or behavioural paradigms to examine the dynamic changes of subunit composition. Finally, physiological implications of such regulation of subunit composition will be investigated by genetic manipulation of mice combined with electrophysiological and behavioural analyses. This work will demonstrate unprecedented views of the subunit composition in situ and provide new insights into how regulation of subunit composition contributes to synaptic plasticity and animal behaviour.

2 481 437 €

Start date: 2016-07-01, End date: 2021-06-30