ERC FUNDED PROJECTS

Brain metastases represent a major therapeutic challenge. Despite significant breakthroughs in targeted therapies, survival rates of patients with brain metastases remain poor. Nowadays, discovery, development and evaluation of new therapies are performed on human cancer cells grown in 2D on rigid plastic plates followed by in vivo testing in immunodeficient mice. These experimental settings are lacking and constitute a fundamental hurdle for the translation of preclinical discoveries into clinical practice. We propose to establish 3D-printed models of brain metastases (Aim 1), which include brain extracellular matrix, stroma and serum containing immune cells flowing in functional tumor vessels. Our unique models better capture the clinical physio-mechanical tissue properties, signaling pathways, hemodynamics and drug responsiveness. Using our 3D-printed models, we aim to develop two new fronts for identifying novel clinically-relevant molecular drivers (Aim 2) followed by the development of precision nanomedicines (Aim 3). We will exploit our vast experience in anticancer nanomedicines to design three therapeutic approaches that target various cellular compartments involved in brain metastases: 1) Prevention of brain metastatic colonization using targeted nano-vaccines, which elicit antitumor immune response; 2) Intervention of tumor-brain stroma cells crosstalk when brain micrometastases establish; 3) Regression of macrometastatic disease by selectively targeting tumor cells. These approaches will materialize using our libraries of polymeric nanocarriers that selectively accumulate in tumors. This project will result in a paradigm shift by generating new preclinical cancer models that will bridge the translational gap in cancer therapeutics. The insights and tumor-stroma-targeted nanomedicines developed here will pave the way for prediction of patient outcome, revolutionizing our perception of tumor modelling and consequently the way we prevent and treat cancer.

2 353 125 €

Start date: 2019-04-01, End date: 2024-03-31

State-of-the-art microscopy and diffraction imaging provides insight into the atomic and sub-atomic structure of matter. They permit determination of the positions of atoms in a crystal lattice or in a molecule as well as the distribution of electrons inside atoms. State-of-the-art time-resolved spectroscopy with femtosecond and attosecond resolution provides access to dynamic changes in the atomic and electronic structure of matter. Our proposal aims at combining these two frontier techniques of XXI century science to make a long-standing dream of scientist come true: the direct observation of atoms and electrons in their natural state: in motion. Shifts in the atoms positions by tens to hundreds of picometers can make chemical bonds break apart or newly form, changing the structure and/or chemical composition of matter. Electronic motion on similar scales may result in the emission of light, or the initiation of processes that lead to a change in physical or chemical properties, or biological function. These motions happen within femtoseconds and attoseconds, respectively. To make them observable, we need a 4-dimensional (4D) imaging technique capable of recording freeze-frame snapshots of microscopic systems with picometer spatial resolution and femtosecond to attosecond exposure time. The motion can then be visualized by slow-motion replay of the freeze-frame shots. The goal of this project is to develop a 4D imaging technique that will ultimately offer picometer resolution is space and attosecond resolution in time.

2 500 000 €

Start date: 2010-03-01, End date: 2015-02-28

Extreme astrophysical events such as relativistic flows, cataclysmic explosions and black hole accretion are one of the key areas for astrophysics in the 21st century. The extremes of physics experienced in these environments are beyond anything achievable in any laboratory on Earth, and provide a unique glimpse at the laws of physics operating in extraordinary regimes. All of these events are associated with transient radio emission, a tracer both of the acceleration of particles to relativistic energies, and coherent emitting regions with huge effective temperatures. By studying radio bursts from these phenomena we can pinpoint the sources of explosive events, understand the budget of kinetic feedback by explosive events in the ambient medium, and probe the physical state of the universe back to the epoch of reionisation, less than a billion years after the big bang. In seeking to push back the frontiers of extreme astrophysics, I will use a trio of revolutionary new radio telescopes, LOFAR, ASKAP and MeerKAT, pathfinders for the Square Kilometre Array, and all facilities in which I have a major role in the search for transients. I will build an infrastructure which transforms their combined operations for the discovery, classification and reporting of transient astrophysical events, over the whole sky, making them much more than the sum of their parts. This will include development of environments for the coordinated handling of extreme astrophysical events, in real time, via automated systems, as well as novel techniques for the detection of these events in a sea of noise. I will furthermore augment this program by buying in as a major partner to a rapid-response robotic optical telescope, and by cementing my relationship with an orbiting X-ray facility. This multiwavelength dimension will secure the astrophysical interpretation of our observational results and help to revolutionise high-energy astrophysics via a strong scientific exploitation program.

2 999 847 €

Start date: 2011-07-01, End date: 2017-06-30

Developing new therapeutic strategies for heart regeneration is a major goal for cardiac biology and medicine. While cardiomyocytes can be generated from human pluripotent stem (hPSC) cells in vitro, it has proven difficult to use these cells to generate a large scale, mature human heart ventricular muscle graft on the injured heart in vivo. The central objective of this proposal is to optimize the generation of a large-scale pure, fully functional human ventricular muscle patch in vivo through the self-assembly of purified human ventricular progenitors and the localized expression of defined paracrine factors that drive their expansion, differentiation, vascularization, matrix formation, and maturation. Recently, we have found that purified hPSC-derived ventricular progenitors (HVPs) can self-assemble in vivo on the epicardial surface into a 3D vascularized, and functional ventricular patch with its own extracellular matrix via a cell autonomous pathway. A two-step protocol and FACS purification of HVP receptors can generate billions of pure HVPs- The current proposal will lead to the identification of defined paracrine pathways to enhance the survival, grafting/implantation, expansion, differentiation, matrix formation, vascularization and maturation of the graft in vivo. We will captalize on our unique HVP system and our novel modRNA technology to deliver therapeutic strategies by using the in vivo human ventricular muscle to model in vivo arrhythmogenic cardiomyopathy, and optimize the ability of the graft to compensate for the massive loss of functional muscle during ischemic cardiomyopathy and post-myocardial infarction. The studies will lead to new in vivo chimeric models of human cardiac disease and an experimental paradigm to optimize organ-on-organ cardiac tissue engineers of an in vivo, functional mature ventricular patch for cardiomyopathy

2 149 228 €

Start date: 2017-12-01, End date: 2022-11-30