Cancer Research - Europa

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DIAMONDS Dedicated Integration and Modelling of Novel Data and Prior Knowledge to Enable Systems Biology Summary We will demonstrate the power of a systems biology approach to study the regulatory network structure of the most fundamental biological process in eukaryotes: the cell cycle. An integrative approach will be applied to build a basic model of the cell cycle in four diff erent species including S. cerevisiae (budding yeast), S. pombe (fi ssion yeast), A. thaliana (weed, model plant) and human cells. To do this, a consortium has been assembled of leaders in the fi elds of cell cycle biology, functional genomic technologies, database design and development, data analysis and integration technology, as well as modelling and simulation approaches. The project combines a number of complementary data sets toward an advanced mining and modelling environment, designed to assist the biologist in building and amending hypotheses, and to help the investigator when designing new experiments to challenge these hypotheses. By doing these simultaneously in widely diff erent organisms, we will ensure that the tools are generally applicable across species. By bringing together biologists, bioinformaticians, biomathematicians and (commercial) software developers in the design phase, we will ensure that a user-friendly, intuitive data analysis environment is created. The main data streams generated de novo within the project concern transcript profi ling and proteomics data (Y2H and TAP). These data will be complemented with information extracted through comparative genomics, and prior knowledge coming from literature mining (text mining tools). The project will bring together a number of existing technologies to build a knowledge warehouse in a relational database designed to contain cell cycle regulatory network information, accessible through an intuitive user platform (GUI) with embedded modelling tools. This platform will enable both top-down and bottom-up hypothesis-driven research, and will serve as a basis to develop more rigorous dynamical models for cell cycle variants. Problem Cell division is regulated by highly conserved genetic networks. Occasionally the cell division machinery becomes unstable, resulting in an uncontrolled proliferation of cells. In humans, the uncontrolled division and growth of cells can lead to cancer. Cell division is also at the core of biomass production and agricultural yield. A better understanding of 26 Keywords | Functional genomics | systems biology | regulatory networks | dynamical modelling | the processes that regulate cell division is therefore of prime importance for human health, welfare and sustainable development. The approach taken by DIAMONDS constitutes a pioneering step toward the application of a systems biology approach for genetic network analysis, and as such will contribute to the maturation of systems biology into a general approach, complementary to the traditional geneby-gene approach. With the rapid increase in genome sequences, published literature and databases on proteomic and transcriptomic data, it is obvious that integrative analysis, bringing together various complementary data types for the identifi cation of network motifs, should be tested on well-defi ned biological models to assess the potential of a systems biology approach. Aim The overarching objective of this multidisciplinary project is to demonstrate the power of a systems biology approach to study fundamental biological processes. We focus on eukaryotic cell cycle regulation, and will develop and implement a computational model that will function as a hypothesisgenerating engine in a systems biology ‘wet-lab’ environment. The work will be done in a number of wet-labs and dry labs, on yeast, plant and human cells, to make sure that the approach is validated across widely diff erent organisms. The main target of the project consists of two parts: • a cell cycle knowledge base and an integrated platform of data mining, modelling and simulation tools that will allow the integrated analysis of that data in a systems biology approach; • the development of a basic model, the use of this model to design new experiments, the production and analysis of novel data, and the integration of these into a refi ned model. The knowledge base and tools will be made available and introduced to the European research community. The principle method to reach this target is to harvest and/ or produce a large body of cell cycle-related biological knowledge. This will function as the central resource for the modelling and simulation environment that will be developed. As mentioned above, the knowledge warehouse will constitute one of the major deliverables of the project, enabling future hypothesis-driven research. The project will showcase the fact that a systems biology approach towards analysis of a fundamental biological process can in fact become mature today, and hinges on an integrated data analysis pipeline, extended with modelling and simulation tools. The essential elements of such a pipeline will be: functional genomics data production (transcriptome and proteome); literature mining; comparative analysis of genes and networks; a visualisation, modelling and simulation environment, and a web service-based data integration layer. CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Expected results We will construct an integrated toolbox for the analysis of functional genomics data, and the modelling of cell cycle information for simulation purposes. We will also deliver a knowledge base (GIN-db) containing detailed information about core cell cycle genes. Potential applications The concerted eff orts in DIAMONDS will allow extensive data integration and modelling, and will deliver new insights in cell cycle regulation and the mechanisms that prevent the uncontrolled proliferation of cells, opening the way to novel anti-tumour drugs and strategies. The potential for applications of life sciences and biotechnology promises to be a growing source of wealth creation in the future, leading to the creation of jobs, particularly in the areas of highly skilled labour, and new opportunities for investment in further research. Coordinator Martin Kuiper Dept. of Biology Faculty of Sciences and Technology NTNU Trondheim, Norway martin.kuiper@bio.ntnu.no Partners Kristian Helin University of Copenhagen Copenhagen, Denmark Denis Thieffry Université de la Méditerranée Marseille, France Søren Brunak Technical University of Denmark Copenhagen, Denmark Alvis Brazma European Bioinformatics Institute Cambridge, United Kingdom Michal Linial The Hebrew University of Jerusalem Jerusalem, Israel Eivind Hovig PubGene AS Oslo, Norway Marta Acilu Noray Bioinformatics, S.L. Bilbao, Spain Alfonso Valencia The National Centre of Biotechnology Madrid, Spain Jurg Bahler The Wellcome Trust, Sanger Institute Cambridge, United Kingdom Project number LSHG-CT-2004-512143 EC contribution € 2 500 000 Duration 36 months Starting date 01/01/2005 Instrument STREP Project website www.SBcellcycle.org BIOLOGY 27
Page 1 and 2: PROJECT SYNOPSES CANCER RESEARCH PR
Page 3 and 4: CANCER RESEARCH PROJECTS FUNDED UND
Page 5 and 6: TABLE OF CONTENTS FOREWORD - CANCER
Page 7 and 8: Prevention 97 EPIC 98 EUROCADET 100
Page 9 and 10: CANCER: COMBATING A COMPLEX DISEASE
Page 11 and 12: Biology Cancer is a disease ethat t
Page 13 and 14: p53 activators ASPP Partner 5 NFkap
Page 15 and 16: Keywords | Angiogenesis | vasculoge
Page 17 and 18: Keywords | Tumour-host interactions
Page 19 and 20: Keywords | Breast | metastasis | ge
Page 21 and 22: Keywords | Identifi cation of novel
Page 23 and 24: Keywords | Systems biology | modell
Page 25 and 26: Keywords | Oncology | anticancer th
Page 27: • public health research coupled
Page 31 and 32: Potential applications Our DNA is u
Page 33 and 34: Microscopic examination of tissue s
Page 35 and 36: Pluripotent embryonic stem cells ar
Page 37 and 38: • Decryption of the leukaemia cel
Page 39 and 40: • identifi cation of molecular ta
Page 41 and 42: A B C LT-HSC CSC The Cancer Stem Ce
Page 43 and 44: X-ray diff raction of target drug c
Page 45 and 46: using pathway-specifi c reporter ce
Page 47 and 48: Keywords | Kinases | pediatric panc
Page 49 and 50: Keywords | Lymphangiogenesis | angi
Page 51 and 52: Keywords | Breast cancer | metastas
Page 53 and 54: Keywords | Mitosis | phosphorylatio
Page 55 and 56: Keywords | Therapy | genome | telom
Page 57 and 58: Keywords | Multiple myeloma | cance
Page 59 and 60: Keywords | p53 tumour suppressor |
Page 61 and 62: Development of eff ective anti-canc
Page 63 and 64: Coordinator Patrick A. Curmi INSERM
Page 65 and 66: Drosophila as a model system for tu
Page 67 and 68: Normal cell growth and epithelial l
Page 69 and 70: effi ciently with cancer cell proli
Page 71 and 72: A high-throughput assay of transcri
Page 73 and 74: Coordinator Ewa Sikora Nencki Insti
Page 75 and 76: Expected results The SIROCCO consor
Page 77 and 78: Keywords | Epigenetics | gene regul
Page 79 and 80:
Keywords | Hereditary | tricarboxyl
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Keywords | HSV-1 | hepatocellular c
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Keywords | Apoptosis | autophagy |
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Keywords | Tumour | host | signalli
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Aetiology The uncontrolled cell gro
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Coordinator Rosalind Eeles Reader i
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The parallelogram approach in CARCI
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Keywords | Melanoma | genetics | na
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Keywords | Virus | bacteria | HPV |
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Keywords | Breast | prostate | gene
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Prevention The fact that preventing
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Coordinator Elio Riboli Imperial Co
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Coordinator Jan Willem Coebergh Joh
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Coordinator Jose M a Benlloch Conse
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BAMOD Breath-Gas Analysis for Molec
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BioCare Molecular Imaging for Biolo
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These centres of excellence will in
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Expected results Optimise the benef
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114 Cell proliferation and apoptosi
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COBRED Colon and Breast cancer Diag
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DASIM Diagnostic Applications of Sy
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Expected results Primarily, the res
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Coordinator John A. Foekens Dept. o
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124 Aim Drop-Top has two major obje
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Coordinator Gorka Ochoa Progenika B
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Expected results The E.E.T.-Pipelin
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e developed by eTUMOUR is likely to
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Coordinator Angel Porgador Ben-Guri
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• the design of a compact assembl
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Potential applications We believe t
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Tumor initiation, progression to ma
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MolDiag-Paca Novel Molecular Diagno
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NEMO Nano based capsule-Endoscopy w
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OVCAD Ovarian Cancer - Diagnosis of
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P-MARK Validation of recently devel
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POC4life Multiparametric quantum do
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PROMET Prostate cancer molecular-or
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Micrometastasis in the bone marrow.
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and pharmaco-kinetics studies. This
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Coordinator Raffaella Giavazzi Isti
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• Development of tools for diagno
Page 163 and 164:
Treatment Two major problems when t
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Coordinator Lluis M. Mir UMR 8121 C
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Potential applications ANGIOSTOP ha
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Green-fl uorescence protein- expres
Page 171 and 172:
Coordinator Robert Hawkins Universi
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Expected results The BACULOGENES pr
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descriptors of the molecules to be
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Keywords | Therapeutic vaccine | im
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Keywords | Cancer chemotherapy | dr
Page 181 and 182:
Keywords | Children | cancer | leuk
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Chimaeric TCR shown in context of n
Page 185 and 186:
Andrea Splendiani Leaf Bioscience s
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Coordinator Anne O’Garra The Medi
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Coordinator Jacques Bartholeyns IDM
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Structure Driven Drug Design The in
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• acquire fundamental knowledge a
Page 195 and 196:
Terry Jones Victoria University of
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Potential applications The use of t
Page 199 and 200:
groups and management structures. T
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T. Barbui Azienda Ospedaliera-Osped
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Keywords | Mantle cell lymphoma | t
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Keywords | Hypoxia | HIF | pericell
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Keywords | Radiation-induced compli
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Keywords | Gene therapy | adenoviru
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Keywords | Dependence receptors | a
Page 213 and 214:
Keywords | Photodynamic therapy | a
Page 215 and 216:
Keywords | Ovarian cancer | thymidy
Page 217 and 218:
Keywords | Quality assurance | clin
Page 219 and 220:
Keywords | Circadian | clocks | cel
Page 221 and 222:
Keywords | Anticancer therapy | onc
Page 223 and 224:
Coordinator Monika Lusky Transgene
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6 000 women over a three-year perio
Page 227 and 228:
Keywords | Solid tumours | apoptosi
Page 229 and 230:
Keywords | Lymphoma | leukaemia | v
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Coordinator Riccardo Dolcetti Centr
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CCPRB Cancer Control using Populati
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EPCRC The European Palliative Care
Page 238 and 239:
EUROCAN+PLUS Feasibility Study for
Page 240 and 241:
EUSTIR A European strategy for the
Page 242 and 243:
NORMOLIFE Development of new therap
Page 245 and 246:
Scientifi c Model Systems The compl
Page 247 and 248:
Performance of benchmarking exercis
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• markers correlating with the im
Page 251 and 252:
Indices - Keywords Indices - Partne
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● disease markers 131 ● DNA dam
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● renal 77 ● replication 219
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Bos, Nico A. 56 Boskovic, Darinka 2
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Geley, Stephan 159 Georgopoulos, Li
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Lingner, Joachim 54 Linial, Michal
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Ragno, Pia 115 Rainford, Martyn 92
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Vernos, Isabelle 22 Veronesi, Umber
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● Centre Hospitalier Universitair
Page 269 and 270:
● IFOM - Fondazione Istituto FIRC
Page 271 and 272:
● National University of Ireland
Page 273 and 274:
● University of Bari 174 ● Univ
Page 275 and 276:
HOW TO OBTAIN EU PUBLICATIONS Our p
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