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

Owing to their visual essence and status as a popular, modern medium, comics – newspaper strips, comics magazines and graphic novels – provide valuable insight into the transformation of collective consciousness. This project advances the hypothesis that children in comics are distinctive embodiments of the complex experience of modernity, channeling and tempering modern anxieties and incarnating the freedom denied to adults. In testing this hypothesis, the project constructs the first intercultural history of children in European comics, tracing the changing conceptualizations of child protagonists in popular comics for both children and adults from the mid-19th century to the present. In doing so, it takes key points in European history as well as the history of comics into account. Assembling a team of six multilingual researchers, the project uses an interdisciplinary methodology combining comics studies and childhood studies while also incorporating specific insights from cultural studies (history of family life, history of public life, history of the body, affect theory and scholarship on the carnivalesque). This enables the project to analyze the transposition of modern anxieties, conceptualizations of childishness, child-adult power relations, notions of liberty, visualizations of the body, family life, school and public life as well as the presence of affects such as nostalgia and happiness in comics starring children. The project thus opens up a new field of research lying at the intersection of comics studies and childhood studies and illustrates its potential. In studying popular but often overlooked comics, the project provides crucial historical and analytical material that will shape future comics criticism and the fields associated with childhood studies. Furthermore, the project’s outreach activities will increase collective knowledge about comic strips, which form an important, increasingly visible part of cultural heritage.

1 452 500 €

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

In contrast to human or rodent embryos, ungulate embryos do not implant into the uterus right after blastocyst hatching. Before implantation, the hatched ungulate blastocyst must undergo dramatic morphological changes characterized by cell differentiation, proliferation and migration processes leading to the development of extra-embryonic membranes, the appearance of a flat embryonic disc and gastrulation. This prolonged preimplantation development is termed conceptus elongation and deficiencies on this process constitute the most frequent cause of reproductive failures in ungulates, including the 4 most relevant mammalian livestock species in Europe. The purpose of this project is to elucidate the factors involved in conceptus elongation by gene editing and in vitro culture approaches. A first objective will be to identify key genes involved in differentiation processes by RNA-seq analysis of different embryo derivatives from bovine conceptuses at different developmental stages. Subsequently, the function of some of the genes identified as well as others known to play a crucial role in mouse development or putatively involved in embryo-maternal interactions will be assessed. For this aim, bovine embryos in which a candidate gene has been ablated (KO) will be generated by CRISPR and transferred to recipient females to assess in vivo the function of such particular gene on conceptus development. A second set of experiments pursue the development of an in vitro system for conceptus elongation that would bypass the requirement for in vivo experiments. For this aim we will perform metabolomics and proteomics analyses of bovine uterine fluid at different stages and will use these data to rationally develop a culture system able to sustain conceptus development. The knowledge generated by this project will serve to develop strategies to enhance farming profitability by reducing embryonic loss and to understand Developmental Biology questions unanswered by the mouse model.

1 480 880 €

Start date: 2017-10-01, End date: 2022-09-30

This five-year project aims to generate a paradigm shift in the understanding of Graeco-Roman and Late Antique communication. Non-literary, ‘documentary’ texts from Ancient Egypt such as letters, petitions and contracts have provided and continue to provide a key witness for our knowledge of the administration, education, economy, etc. of Ancient Egypt. This project argues that since documentary texts represent originals, their external characteristics should also be brought into the interpretation: elements such as handwriting, linguistic register or writing material transmit indirect social messages concerning hierarchy, status, and power relations, and can therefore be considered ‘semiotic resources’. The project’s driving hypothesis is that communicative variation – variation that is functionally insignificant but socially significant (e.g. there are ~ there’s ~ it’s a lot of people) – enables the expression of social meaning. The main aim of this project is to analyse the nature of this communicative variation. To this end, a multidisciplinary team of six researchers (one PI, one post-doc, and four PhD’s) will apply recent insights form socio-semiotic and socio-linguistic theory to a corpus of Graeco-Roman and Late Antique documentary texts (I – VIII AD) by means of a three-level approach: (i) an open-access database of annotated documentary texts will be created; (ii) the ‘semiotic potential’ of the different semiotic resources that play a role in documentary writing will be analysed; (iii) the interrelationships between the different semiotic resources will be studied. The project will have a significant scientific impact: (i) it will be the first to offer a holistic perspective towards the ‘meaning’ of documentary texts; (ii) the digital tool will open up new ways to investigate Ancient texts; (iii) it will make an important contribution to current socio-semiotic and socio-linguistic research; (iv) it will provide new insights about humans as social beings.

1 476 250 €

Start date: 2018-06-01, End date: 2023-05-31

A fundamental problem in the study of dynamical systems is to ascertain whether the effect of a perturbation on an integrable Hamiltonian system accumulates over time and leads to a large effect (instability) or it averages out (stability). Instabilities in nearly integrable systems, usually called Arnold diffusion, take place along resonances and by means of a framework of partially hyperbolic invariant objects and their homoclinic and heteroclinic connections. The goal of this project is to develop new techniques, relying on the role of invariant manifolds in the global dynamics, to prove the existence of physically relevant instabilities and homoclinic phenomena in several problems in celestial mechanics and Hamiltonian Partial Differential Equations. The N body problem models the interaction of N puntual masses under gravitational force. Astronomers have deeply analyzed the role of resonances in this model. Nevertheless, mathematical results showing instabilities along them are rather scarce. I plan to develop a new theory to analyze the transversal intersection between invariant manifolds along mean motion and secular resonances to prove the existence of Arnold diffusion. I will also apply this theory to construct oscillatory motions. Several Partial Differential Equations such as the nonlinear Schrödinger, the Klein-Gordon and the wave equations can be seen as infinite dimensional Hamiltonian systems. Using dynamical systems techniques and understanding the role of invariant manifolds in these Hamiltonian PDEs, I will study two type of solutions: transfer of energy solutions, namely solutions that push energy to arbitrarily high modes as time evolves by drifting along resonances; and breathers, spatially localized and periodic in time solutions, which in a proper setting can be seen as homoclinic orbits to a stationary solution.

1 100 348 €

Start date: 2018-01-01, End date: 2023-12-31

Meteorites are privileged witnesses of solar system accretion processes and early planetary evolution. Short-lived radioactive chronometers are particularly adapted in dating and understanding these early differentiation processes. This proposal is dedicated to two main questions: (1) what is the initial composition of the solar system and terrestrial planets?; (2) having refined these parameters, how and when silicate bodies differentiated? Among short-lived chronometers, the system 146Sm-142Nd is particularly adapted to solve these questions. While it is generally assumed that the global bulk composition of Earth and other terrestrial planets is chondritic for refractory elements such as Sm and Nd, it has recently been shown that the 142Nd/144Nd values display a systematic and reproducible bias between all the chondrites and the average composition of the Earth, and also possibly of other planets. Several hypotheses have been proposed: (i) there is an enriched reservoir hidden deep in Earth, with a composition balancing the currently observed terrestrial composition in order to get a global chondritic composition for the Earth. (ii) The Earth and other terrestrial planets are non-chondritic for their composition in refractory elements. (iii) Nucleosynthetic anomalies have modified the isotopic composition measured in chondrites. (iv) The starting parameters of the 146Sm-142Nd system are not well defined. However, this last point has never been carefully evaluated. The main scientific strategy of this proposal is based on reinvestigating with the best precision ever achieved the starting parameters of the 146Sm-142Nd systematic using the oldest objects of the solar system: Ca-Al inclusions and chondrules. The final goal of the present proposal is to determine if Earth and other planets are chondritic or not, and to understand the implications of their refined starting composition on their geological evolution in terms of early planetary differentiation.

1 485 299 €

Start date: 2014-03-01, End date: 2019-02-28

One of the most striking demonstrations of experience-dependent plasticity comes from studies of blind individuals showing that the occipital cortex (traditionally considered as purely visual) massively changes its functional tuning to support the processing of non-visual inputs. These mechanisms of crossmodal plasticity, classically considered compensatory, inevitably raise crucial challenges for sight-restoration. The neglected relation between crossmodal plasticity and sight-recovery will represent the testing ground of MADVIS in order to gain important novel insights on how specific brain regions become, stay and change their functional tuning toward the processing of specific stimuli. The main goal of MADVIS is therefore to make a breakthrough on two fronts: (1) understanding how visual deprivation at different sensitive periods in development affects the functional organization and connectivity of the occipital cortex; and (2) use the fundamental knowledge derived from (1) to test and predict the outcome of sight restoration. Using a pioneering interdisciplinary approach that crosses the boundaries between cognitive neurosciences and ophthalmology, MADVIS will have a large impact on our understanding of how experience at different sensitive periods shapes the response properties of specific brain regions. Finally, in its attempt to fill the existing gap between crossmodal reorganization and sight restoration, MADVIS will eventually pave the way for a new generation of predictive surveys prior to sensory restoration.

1 488 987 €

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

The Internet was expected to make citizens considerably more informed and better able to hold politicians and powerful interests accountable. Many predicted it would also effectively complement traditional media and improve news reporting. These expectations have not been met. There is no evidence that citizens have become more informed; they have, however, become more ideologically polarized, possibly due to online media overexposing users to like-minded content. At the same time, traditional media are struggling: competition from online platforms has slashed advertising revenues forcing newspapers to close or downsize. These changes risk undermining the quality of reporting and making media more vulnerable to capture by special interests. My project examines how the Internet has transformed the way news is produced and disseminated, both directly and through its influence on traditional media, and its ultimate effect on media independence and content quality. To this end, I tackle four distinct but intertwined questions. First, I examine to what extent Google search results are tailored to users’ political views, and whether personalized results increase ideological polarization. Second, I study how lower advertising revenues affect newspapers’ organization and content quality by exploiting the staggered introduction of advertising platform Craigslist across the US. Third, I examine how media dependence on advertisers influences news bias by testing the relationship between advertising spending by car manufacturers and coverage of car safety recalls in US newspapers. Finally, I study how the dependence of media on banks affects coverage of financial issues; focusing on Europe’s sovereign debt crisis, I test whether newspapers linked to banks with higher exposure to risky debt endorsed different crisis-management measures. My results will shed light on the deep transformations the media industry is undergoing and their implications for the quality of democracy.

1 485 500 €

Start date: 2018-11-01, End date: 2023-10-31

"The novel is today the most popular literary genre worldwide. Its early history has not been written yet. In order to enhance our understanding of this history (both conceptually and cross-culturally), this project offers the first comprehensive reconstruction and interpretation of the persistence of ancient novelistic material in hagiographical narrative traditions in the Mediterranean in Late Antiquity and the early Middle Ages (4th-12th cent.). This period constitutes a blind spot on the radar of scholars working on the history of the novel, who conceptualize it, much to the detriment of the study of narrative in subsequent periods, as an ‘empty’ interim period between the latest ancient representatives of the genre (ca. 3rd-4th cent.) and its re-emergence in 11th/12th-century Byzantium and 11th-century Persia. This project, on the other hand, advances the hypothesis that different hagiographical traditions throughout Late Antiquity and the early Middle Ages were impacted (directly or indirectly) by ancient novelistic influences of different kinds and adopted, rehearsed, re-used and adapted them to various degrees as tools for the representation of saints as heroes/heroines. In this sense, constructions of heroism in these traditions should be understood to varying degrees as ‘novelistic’ and raise crucial issues about fictionalization and the texts’ own implicit conceptualizations of fiction. Three stages of the project will test different aspects of this hypothesis. Firstly, the project will chart for the first time all novelistic influences in the hagiographical corpus texts. Secondly, it will analyze the impact of these influences on constructions of heroism in specific hagiographical traditions (mainly Latin, Greek and Syriac Martyr Acts, hagiographical romances and saints’ Lives) and examine implications for notions of fictionalization and/or strategies for enhancing verisimilitude and authenticity. Finally, diachronic and cross-cultural dimensions of the research hypothesis will be articulated through the study of continuity of hagiographical traditions (and their constructions of heroism) in narrative genres from the 11th and 12th centuries in the West (medieval romance), Byzantium (novels) and the East (Persian romance). By generating an improved understanding of the impact of ancient novelistic material in different hagiographical traditions throughout Late Antiquity and the early Middle Ages, this project aims to contribute not just to the history of the idea of fiction but also to the study of hagiography, the early history of the novel and to all disciplines that study these literary genres."

1 467 300 €

Start date: 2014-02-01, End date: 2019-01-31

PROTEUS studies main strategies devised by Western philosophy in representing time in cosmology. It aims at modifying current metaphysics and its relationship with cosmology in the light of recent scientific debates in quantum gravity and quantum cosmology, thereby boosting a new research field in history and philosophy of cosmology. The project is based on two hypotheses: 1) the history of philosophy reveals a guideline that can be traced back to Plato and that characterizes physical and metaphysical approaches to the question of the beginning of the universe in terms of a tension between fundamentality and non-fundamentality of time; 2) there is a conceptual problematic assumption in Western culture and it consists in shaping the problem of the origin of the world as a problem of thinking about the very same conditions of possibility of the origin of a process that is not in time. The project spells out the conceptual roots of current representations of time in quantum gravity and quantum cosmology and highlights the conceptual break that they provide with respect to philosophical concepts of time portrayed in previous systems. PROTEUS explores in detail the notions of time and the paradoxes emerging in the philosophy and cosmology of Plato and Kant and identifies the fundamental characters of emergent time in current quantum gravity theories. In identifying these fundamental features, PROTEUS produces conceptual innovation in metaphysics in such a way that philosophical investigation is complementary to the development of current theories. PROTEUS elaborates alternative argument(s) to anthropic principle, as well as new categories accounting for the notion of ‘contingent necessity’ of the world. The research team includes members from different backgrounds (philosophy, mathematics and physics) and will promote the application of a new methodology emphasizing the relevance of the history of philosophy and the actual interaction between philosophers and scientists.

1 418 869 €

Start date: 2018-09-01, End date: 2023-08-31

"Cancer cells are defective in vital cell functions such as cell cycle control and response to growth signals. We found that cancer cells acquire defects in yet another vital function: translation of mRNA into proteins. We saw that 9.8% of children with T-cell leukemia (T-ALL) harbor acquired mutations in the ribosome, the cellular protein translation factory. We found mutations in RPL10, RPL5 and RPL22, 3 proteins of the large 60S ribosomal subunit. Strikingly, 6.5% of T-ALL patients had the same RPL10 R98S missense mutation. Although congenital ribosome defects were previously linked to higher cancer risk, the concept that defects in the ribosome are acquired during life and are selected for in cancer is novel. In addition, it is currently not understood by what mechanism ribosome defects are carcinogenic. Patients with inherited ribosome defects are predisposed to all types of cancer. Therefore, other cancers than T-ALL may show acquired defects in the ribosome and I want to explore the prevalence of acquired ribosome defects in various cancer types. Second, I want to explore by which mechanism ribosome mutations promote cancer. Initially, I will focus on the RPL10 R98S mutation, the most frequent acquired ribosome defect we found so far. We will test the effect of RPL10 R98S on cell behavior parameters such as self-renewal capacity and resistance to apoptosis. I hypothesize that altered translation of a subset of cellular mRNAs, including mRNAs coding major tumor suppressors or oncogenes, may explain the oncogenic action of RPL10 R98S. Therefore, we will identify all mRNAs with altered translation efficiency or fidelity in RPL10 R98S cells. In addition, we will test if RPL10 R98S promotes cancer by altering extra-ribosomal roles of RPL10 or by driving inactivation of the TP53 pathway. Finally, acquired ribosome defects may represent a novel target for cancer therapy and we will test if ribosome defective cancer cells are hypersensitive to translation inhibitors."

1 497 038 €

Start date: 2014-01-01, End date: 2018-12-31