ERC FUNDED PROJECTS

The actual view of cellular transformation and cancer progression supports the notion that cancer cells must undergo metabolic reprogramming in order to survive in a hostile environment. This field has experienced a renaissance in recent years, with the discovery of cancer genes regulating metabolic homeostasis, in turn being accepted as an emergent hallmark of cancer. Prostate cancer presents one of the highest incidences in men mostly in developed societies and exhibits a significant association with lifestyle environmental factors. Prostate cancer recurrence is thought to rely on a subpopulation of cancer cells with low-androgen requirements, high self-renewal potential and multidrug resistance, defined as cancer-initiating cells. However, whether this cancer cell fraction presents genuine metabolic properties that can be therapeutically relevant remains undefined. In CancerMetab, we aim to understand the potential benefit of monitoring and manipulating metabolism for prostate cancer prevention, detection and therapy. My group will carry out a multidisciplinary strategy, comprising cellular systems, genetic mouse models of prostate cancer, human epidemiological and clinical studies and bioinformatic analysis. The singularity of this proposal stems from the approach to the three key aspects that we propose to study. For prostate cancer prevention, we will use our faithful mouse model of prostate cancer to shed light on the contribution of obesity to prostate cancer. For prostate cancer detection, we will overcome the consistency issues of previously reported metabolic biomarkers by adding robustness to the human studies with mouse data integration. For prostate cancer therapy, we will focus on a cell population for which the metabolic requirements and the potential of targeting them for therapy have been overlooked to date, that is the prostate cancer-initiating cell compartment.

1 498 686 €

Start date: 2013-11-01, End date: 2019-10-31

Neuronal plasticity is an important mechanism for memory and cognition, and also fundamental to fine-tune perception to the environment. It has long been thought that sensory neural systems are plastic only in very young animals, during the so-called “critical period”. However, recent evidence – including work from our laboratory – suggests that the adult brain may retain far more capacity for plastic change than previously assumed, even for basic visual properties like ocular dominance. This project probes the underlying neural mechanisms of adult human plasticity, and investigates its functional role in important processes such as response optimization, auto-calibration and recovery of function. We propose a range of experiments employing many experimental techniques, organized within four principle research lines. The first (and major) research line studies the effects of brief periods of monocular deprivation on functional cortical reorganization of adults, measured by psychophysics (binocular rivalry), ERP, functional imaging and MR spectroscopy. We will also investigate the clinical implications of monocular patching of children with amblyopia. Another research line looks at the effects of longer-term deprivation, such as those induced by hereditary cone dystrophy. Another examines the interplay between plasticity and visual adaptation in early visual cortex, with techniques aimed to modulate retinotopic organization of primary visual cortex. Finally we will use fMRI to study development and plasticity in newborns, providing benchmark data to assess residual plasticity of older humans. Pilot studies have been conducted on most of the proposed lines of research (including fMRI recording from alert newborns), attesting to their feasibility and the likelihood of them being completed within the timeframe of this grant. The PI has considerable experience in all these research areas.

2 493 000 €

Start date: 2014-05-01, End date: 2019-04-30

The “Cancer Stem Cell (CSC) Hypothesis” postulates that the capacity to maintain tumour growth is owned by rare cancer cells, the CSCs, endowed with self-renewal properties. This hypothesis implies that CSCs must be eliminated to achieve cancer cure. Nevertheless, direct proof is still lacking, and recent findings challenge our concepts of CSCs, showing the limits of the CSC-defining assay (transplantation) and suggesting that CSC-identity might be context-dependent. We found two properties of CSCs self-renewal that are indispensable for the maintenance of an expanding CSC-pool and tumour growth: increased frequency of symmetric divisions, due to inactivation of the p53 tumour suppressor, and increased replicative potential, due to up-regulation of the cell-cycle inhibitor p21. We will now investigate: i) How loss of p53 in tumours leads to expansion of the CSC pool, by testing the hypothesis that p53-loss activates the Myc oncogene which induces CSC-reprogramming of differentiated cancer cells. ii) Whether p53-independent pathways are also implicated, by in vivo shRNA screens of primary tumours or normal progenitors to identify pathways involved, respectively, in CSC self-renewal or inhibition of SC-reprogramming. iii) How p21-induced cell-cycle arrest protects CSCs from self-renewal exhaustion, by investigating regulation of cell-cycle recruitment of quiescent CSCs. iv) Whether activation of p21 in CSCs induces a mutator phenotype, due to its ability to activate DNA repair, by investigating mechanisms of DNA-damage, mutation rates, and relevance of CSC mutations for development of chemoresistance. We will test self-renewal functions in a transplantation-independent assay, based on tumour re-growth in vivo after cytotoxic treatments and “clonal tracking” of re-growing tumours (using barcoded lentiviral libraries). Our long-term goal is the identification of CSC-specific targets that could be used to create the basis for CSC-specific pharmacological intervention.

2 500 000 €

Start date: 2014-07-01, End date: 2019-06-30

Risk and uncertainty are inherent in any decision-making procedure, but while a substantial body of work on the governance of international migration focuses on challenges posed to governance systems, we know remarkably little about the impact of risk and uncertainty on: (i) the cognitive biases of actors within migration governance systems; (ii) the susceptibility of these biases to change; (iii) the relationship between cognitive bias and broader questions of systemic resilience, vulnerability and adaptation and (iv) the similarities and differences in migration governance between major world regions. Each of these is a significant gap in our knowledge of international migration governance. To address this gap this project will focus on the context of decision to ask: what are the causes and consequences of the cognitive biases concerning risk and uncertainty held by actors in migration governance systems? The project will: (i) test the causes and consequences of the ‘frames’ held by actors in migration governance systems, specify the scope for these frames to change and to analyse the likely systemic effects of change on migration governance systems in four major world regions. (ii) develop a comparative regional analysis of the micro-political foundations of migration governance and their implications for system adaptation and change. (iii) significantly advance conceptual and methodological understanding of international migration governance through the use of concepts of systemic adaptation, vulnerability and resilience that bridge behavioural theories of choice with theories of institutional and organisational change. (iv) disseminate the results effectively through a range of appropriate outlets and through engagement with a range of users of the results of this work in academia, policy-making communities, NGOs and the wider public.

2 127 926 €

Start date: 2014-04-01, End date: 2019-03-31