TRANSlational and Functional Onco-Genomics
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Impact & Results
It is of strategic importance for the European biomedical research to coordinate its resources at enabling discovery of new candidate cancer-related genes and developing experimental approaches for their systematic functional and clinical validation. To keep up with advances in genomic sequence and expression data generation, the US and Japan are now hugely accelerating gene functional characterization. TRANSFOG intends to bring momentum to a core of highly strategic functional genomics activities that are critical for acquiring molecular medicine and new drug development capability at the European level.
TRANSFOG will initially focus on basic biological processes involved in cancer progression, for two reasons: (a) progression towards the metastatic phenotype is the actual cause of most cancer-related deaths, and there's no effective way to combat cancer when multiple molecular lesions have altered basic biological functions; (b) most of the participating RUs are world-recognized leaders in this field, for which integration at the European level will provide a structuring effect and allow to achieve the critical mass required for a world-competitive functional genomics project. Indeed, Europe hosts a strong community of top-level researchers studying various aspects of tumour invasive growth, which already share research projects under collaborative grants, and their results in meetings like the EMBO Workshop: "The Invasive Growth Program: Signals and Effectors", which was held at the IRCC (Partner 2) in February 2002. Other RUs provide complementary, top-level competences crucial for integration and technological enabling of the outlined research activities.
A crucial issue in genomics is to develop enabling technologies. TRANSFOG will tackle this issue by developing a series of technologies here briefly outlined.
  • Tools and standards for genomic data sharing will allow merging the results of cancer-oriented genomic screenings carried out by the Consortium or available in databases and generating a prioritized list of candidate cancer genes.
  • Generation/assembly of plasmid collections carrying FL-cDNAs or siRNAs to achieve gain- or loss-of-functions of the identified candidates. Within few years, competitive research will rely on the availability of genome-wide collections enabling systematic gene gain- or loss-of-function and protein-protein interaction studies. Similarly, only high-throughput biochemical and biological assays will take full advantage of such collections, together with bioinformatic resources to handle and mine the data. A great advantage of a smaller collection focussed on cancer gene discovery, like the one proposed here, is that it will enable functional analysis at a mid-throughput level, with a higher probability of success in the timeframe of the project. The know-how developed in the process of generating and employing such collection will provide the basis for competitive, larger-scale studies to be carried out later on at the European level.
The willingness to understand and cure cancer will be the driving force for generating functional genomics technologies specifically aimed at improving management of the oncological patient. Indeed, a more precise evaluation of the tendency of a tumour to give rise to metastases will have a great social impact, in particular to help reduce mortality and, at the same time, reduce overtreatment of patients that would not require aggressive anticancer therapy, and promote direct, early exploration of alternative therapeutic strategies in patients with diagnostic signatures that predict poor prognosis
The Human Genome Project, currently in the phase of sequence assembly and annotation, is tremendously accelerating the description and inventory of the genes potentially involved in physiological and pathological processes. However, a similar turning point is still lacking for highly parallel functional validation of genes identified by genomic exploration. Systematic loss-of-function screenings are currently ongoing on model organisms, including the mouse. Yet, functional redundancy or subtle phenotypes may impair characterization of a consistent number of genes. Moreover, such screenings allow exploration of gene function in the context of the organism, but are hard to direct at defining basic biochemical and biological properties.
Biomedical research is currently facing a historical change in the perspectives and modality of gathering information about gene functions and biological processes. The completion of the human genome sequencing reversed the conventional approach to biomedical discovery, in which understanding a certain biological function required identification of one or more genes involved in that function. The current situation is that thousands of genes have been sequenced but still wait for any functional information to be assigned to them. The fact that genes of unknown function represent over 70% of all genes suggests that current comprehension of most biological and pathological processes, and therefore of cancer, is by far incomplete. In this perspective, systematic exploration of gene function is likely to yield a huge amount of information in the next years. To this aim, new technological platforms have to be developed to increase the throughput of established procedures for functional gene characterization.
The TRANSFOG project will deliver a consistent and integrated amount of functional data on genes of as yet unknown activity and biological role. In the process of reaching this objective, the participating Units will be enabled to set-up truly post-genomic efforts toward systematic gene functional characterization. New technologies will be developed that will allow exploration of gene regulatory networks, protein-protein interactions and high-throughput cell-based evaluation of basic biological functions such as motility, growth, apoptosis, invasion, adhesion, polarization and more complex processes as in vitro epithelial morphogenesis and angiogenesis. The technologies for systematic gene functional characterization developed here will be useful for functional studies involving a variety of physiological and pathological processes, and will be made available to the scientific community in the frame of a collaborative research network. The bioinformatic networking endowed with the project will enable participating Units to share tools for data handling, database exploration and functional gene annotation. It will also facilitate integration of the present network with other EC-funded networks and with the European and global post-genomic community.
OECI week

OECI Week (WG workshops; Scientific Conference and General Assembly) – Budapest, 16 to 18 June 2010.
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