Cancer Research - Europa

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ONCASYM <strong>Cancer</strong> stem cells and asymmetric cell division Summary An intense line of current investigation into cancer is based on the connection between tumourigenesis and stem cell biology. Some tumours may originate from the transformation of normal stem cells, at least in the case of blood, breast, skin, brain, spino-cerebellar and colon cancers. In addition, tumours may contain ‘cancer stem cells’, rare cells with indefinite potential for self-renewal that drive tumourigenesis. Interestingly, the same signalling pathways (TGF-beta/BMP, Wnt and Notch pathways) appear to regulate self-renewal in stem cells and cancer cells. Self-renewal occurs through the asymmetric cell division of stem cells, which thereby generate a daughter stem cell and another daughter cell that contributes to populate the developing organ or the growing tumour. In one of the best understood asymmetric cell division models, the Drosophila nervous system, asymmetry is mediated by a biased Notchdependent signalling event between the two daughter cells. ONCASYM partners have recently shown: • that the process of biased signalling during asymmetric cell division is controlled by endocytosis; • that tumours can be induced in mutants with altered stem-cell asymmetric division. In human normal and cancer stem cells, asymmetric cell division is supposed to take place, but it has not directly been proven yet. Furthermore, the role of biased signalling by endocytosis in these stem cells has not been addressed to date. The aim of this project is threefold: • to screen for genes involved in asymmetric cell division of human cancer stem cells; • to characterise the asymmetric cell division of these stem cells by using these candidate genes as markers; • to study functionally the role of the identifi ed candidate genes during asymmetric cell division of cancer stem cells. Our ultimate goal is to untangle the molecular machinery of cancer stem cell asymmetric division, thereby providing druggable targets for cancer therapy. Problem Cell types within a tumour vary in their ability to form the whole tumour mass. In fact, only very few cells can give rise to all cells present in the tumour. These so-called tumour stem cells have been characterised in a variety of tumours, including leukaemia, breast cancer and brain tumours. Their existence challenges conventional tumour therapy, which is 62 Keywords | Drosophila | breast cancer | colorectal cancer | mammospheres | crypt | tissue array | larval neuroblast | sensory organ precursor | targeted at destroying rapidly proliferating cells. Stem cells often proliferate slowly and might not be eliminated by such therapies, which might explain the high relapse rate observed for some cancers. Alternative therapies that target stem cells are not available. This is partly due to our limited understanding of proliferation control in stem cells and the lack of appropriate cancer models which mimic the development of tumours from defi ned stem cell populations. Aim The goal of this project is to develop new therapeutic strategies that target tumour stem cells. Stem cells are characterised by their ability to divide asymmetrically and thereby form self-renewing and diff erentiating daughter cells at the same time. Even a slight change in the balance between these two cell types could dramatically increase the number of daughter cells created by a stem cell and thereby contribute to tumour formation. Expected results In our project we plan: • to discover the genes involved in asymmetric cell division and tumour suppression in normal and malignant stem cells, using Drosophila as a model system, and to fi nd their human and mouse homologues; • to use this candidate gene list to fi nd markers for the identifi cation of normal and cancer stem cells in the mammary gland and the intestinal crypts and use these markers to image the asymmetric cell division event. Potential applications We will directly translate the acquired knowledge into the clinical practice. • We plan to validate the newly identifi ed ‘stemness’ signature as a clinical tool for genomic grading and prognostic evaluation. This task will be initially accomplished by retrospectively performing meta-analysis, using the currently available public databases as well as the wide collection of cases from our tumour registry. • Tissue microarrays will be used to further validate the relevance of candidate ‘stemness’ genes to the diagnostic routine, by establishing their predictive strength in relation to the common clinical-prognostic parameters. • Prospectively, the identifi ed ‘stemness’ genes will be introduced as ‘biomarkers’ for the clinical and prognostic evaluation of cancer patients enrolled in ad hoc clinical trials at the European Institute of Oncology, even including their use in the procedure of the sentinel node in order to identify the presence of stem cells in metastasis. CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
Drosophila as a model system for tumourigenesis. Transplanted tissue into Drosophila abdomen (black scars) do not cause tumours (labelled in green) unless the transplanted tissue is mutant for factors involved in asymmetric cell division (right fl y). ONCASYM uses this assay as a gene discovery tool for the genes involved in tumourigenesis. Coordinator Marcos Gonzalez-Gaitan Dept. of Biochemistry University of Geneva Geneva, Switzerland gonzalez@mpi-cbg.de Partners Hans Clevers The Netherlands Institute for Developmental Biology Hubrecht Laboratory Royal Netherlands Academy of Sciences Utrecht, The Netherlands Pier Paolo de Fiore Istituto FIRC di Oncologia Molecolare Milan, Italy BIOLOGY Umberto Veronesi European Institute of Oncology Milan, Italy Jürgen Knoblich Institute of Molecular Biotechnology of the Austrian Academy of Sciences Vienna, Austria Cayetano Gonzalez Institut de Reçerca Biomédica Barcelona, Spain Andre Hoekema Galapagos NV Mechelen, Belgium Project number LSHC-CT-2006-037398 EC contribution € 2 823 800 Duration 36 months Starting date 01/10/2006 Instrument STREP Project website www.Oncasym.unige.ch 63
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PROJECT SYNOPSES CANCER RESEARCH PR
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CANCER RESEARCH PROJECTS FUNDED UND
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TABLE OF CONTENTS FOREWORD - CANCER
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Prevention 97 EPIC 98 EUROCADET 100
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CANCER: COMBATING A COMPLEX DISEASE
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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 and 28: • public health research coupled
Page 29 and 30: Expected results We will construct
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: Coordinator Patrick A. Curmi INSERM
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
Page 81 and 82: Keywords | HSV-1 | hepatocellular c
Page 83 and 84: Keywords | Apoptosis | autophagy |
Page 85 and 86: Keywords | Tumour | host | signalli
Page 87 and 88: Aetiology The uncontrolled cell gro
Page 89 and 90: Coordinator Rosalind Eeles Reader i
Page 91 and 92: The parallelogram approach in CARCI
Page 93 and 94: Keywords | Melanoma | genetics | na
Page 95 and 96: Keywords | Virus | bacteria | HPV |
Page 97 and 98: Keywords | Breast | prostate | gene
Page 99 and 100: Prevention The fact that preventing
Page 101 and 102: Coordinator Elio Riboli Imperial Co
Page 103 and 104: Coordinator Jan Willem Coebergh Joh
Page 105: Coordinator Jose M a Benlloch Conse
Page 108 and 109: BAMOD Breath-Gas Analysis for Molec
Page 110 and 111: BioCare Molecular Imaging for Biolo
Page 112 and 113: 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
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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
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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
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Keywords | Children | cancer | leuk
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Chimaeric TCR shown in context of n
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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
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Terry Jones Victoria University of
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Potential applications The use of t
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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
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Keywords | Photodynamic therapy | a
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Keywords | Ovarian cancer | thymidy
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Keywords | Quality assurance | clin
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Keywords | Circadian | clocks | cel
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Keywords | Anticancer therapy | onc
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Coordinator Monika Lusky Transgene
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6 000 women over a three-year perio
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Keywords | Solid tumours | apoptosi
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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
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EUROCAN+PLUS Feasibility Study for
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EUSTIR A European strategy for the
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NORMOLIFE Development of new therap
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Scientifi c Model Systems The compl
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Performance of benchmarking exercis
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• markers correlating with the im
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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
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● IFOM - Fondazione Istituto FIRC
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● National University of Ireland
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● University of Bari 174 ● Univ
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