Download EXPRESSION OF INTEREST Integrated Project Genome

Call for Expression of Interest
EOI.FP6.2002
EXPRESSION OF INTEREST
Integrated Project
Genome-wide screens for genes required for cell migration and metastasis
Prepared by
Dr. Erez Raz, MPI Goettingen, Germany
Core partners
Max-Planck-Institute for Biophysical Chemistry, Goettingen, Germany
Instituto Cajal, Madrid, Spain
Max-Delbrueck-Centrum, Berlin, Germany
Weizmann Institute of Science, Rehovot, Israel
Institute for Cancer Research - University of Torino, Italy
This Expression of Interest was submitted in response to Call EOI.FP6.2002
5th June 2002
1.
Aim of the Proposed Work
The aim of this proposal is to advance the European scientific expertise in the field of tumour metastasis and to
promote the design of novel targets for diagnosis and treatment of cancer.
1.1 Contribution to Priority Thematic Area of Framework 6
This proposal is based on genome-wide analyses and identification of molecules participating in the process of
cell migration in different model organisms. This knowledge will then be applied for the elucidation of gene
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products mediating cellular metastatic processes in human cancer diseases. Such gene products will provide a
basis to develop new drugs to abrogate metastatic processes in the future and for diagnosis of metastatic
potential of tumours. The aim and experimental approaches correspond to priority no. 1.1.2.2 – Combating
cancer.
1.2 Contribution to the European Research Area
The integrated project will combine expertise of several groups that approach the problem of cell migration
using different methodologies in different model organisms. Such a combination will promote the exchange and
utilization of the obtained results among the participating groups and will lead to faster application of the
findings in the field of medicine.
2.
Background to the Proposed Work
Tumour metastasis is the main cause of lethality in cancer patients. Cellular metastasis is based on detachment
of cells from the primary tumour, invasiveness through surrounding tissues and blood vessels and active
migration towards the tissue where secondary tumours develop. In some cases the formation of the secondary
tumour appears to involve directed migration of the cells towards regions which express specific attractants.
Similarly, during normal development many examples exist of cells of different origin that detach from their
original tissue and migrate towards a distinct target tissue. This integrated project is aimed at uncovering basic
mechanisms underlying guided cell migration in embryonic development based on complementary research
approaches implemented in four different model organisms. The starting point in each group is a specific key
gene product/s whose activity has been shown to be involved in guided cell migration. These gene products
include the invasiveness-related gene snail/slug; the germ-cell migration-related gene dead end; stripe, a gene
involved in directing muscle migration; and the superfamily of Semaphorins and Scatter factor. Genome-wide
experimental approaches will be taken by the groups in the integrated project, utilizing the available sequence
of genomes of Drosophila, Mouse, Zebrafish and Human to uncover gene products mediating embryonic
guided cell migration and/or cellular metastasis in humans.
3.
Expected Results
1.
Identification and characterization of gene products involved in epithelial to mesenchymal transition.
2.
Identification and characterization of gene products involved in cell motility.
3.
Identification and characterization of gene products involved in directed cell migration towards an
attracting tissue.
4.
Identification and characterization of gene products involved in cell repulsion.
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Users of these results may be Pharmaceutical/Biotech companies which may develop diagnostic tools to
evaluate the metastatic potential of tumours as well as drugs directed to abrogate the activity of genes identified
in 1-4. Additionally, gene products mediating cellular attraction may be used to deliver specific drugs towards
specific tissue destination, based on the attractant cues.
4.
Activities to Achieve the Proposed Objectives
The work is aimed at characterization of the activity of the migration-related gene products (see above) and
identifying additional key molecules involved in conferring migratory cell behaviour or required for the
migration process will be conducted in the labs by following the migratory behaviour of different cell types in
embryos of different organisms. The results obtained using the different approaches will be communicated
within the group and attempts will be made to determine the relevance of findings made in one system to other
systems. The relevance of the findings to metastasis will be determined by testing their metastatic potential in
nude mice and, in addition, analysing the expression profile of the isolated molecules or their homologues in
tumour cells exhibiting metastatic behaviour.
4.1 Integration Activities
The integration activities can be summarised as follows:
Regular meetings of the groups involved will be conducted where information will be exchanged and decisions
regarding future directions taken. A shared database that will include molecules identified in the different
screens will be established to facilitate fast exchange of results and cloning of homologues in the different
systems.
4.2 Research Activities
The main joint research activities required to achieve the objectives can be summarised as follows:
Screens for genes whose expression is correlated with guided cell migration during embryonic development
will be performed in different organisms and in different cell systems. These screens include: (1)
Transcriptional profiling experiments to identify stripe-dependent, tendon-specific genes required for
attraction/repulsion of migrating muscle cells. (2) Screen to identify genes regulated by snail-family members
that trigger epithelial to mesenchymal transition. (3) Identify genes whose function is important for conferring
migratory behaviour on primordial germ cells in zebrafish by isolating targets of dead end, a gene controlling
primordial germ cells migration in zebrafish, (4) Identify human genes controlled by the superfamily of
Semaphorin and Scatter factor receptors and involved in cell migration events during development and tumour
metastatization. (5) Identify genes that control migration of neural crest cells, glia and neurons during
development of the nervous system in the mouse. It is expected that such a comprehensive approach will result
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in the identification of a major portion of the gene whose function is required for this process. The
communication of results, continuous discussions and exchange of materials will allow the group to quickly
identify factors whose function is required in many systems as well as factors which are required in specific
cells or organisms.
5.
Expertise Needed to Achieve Objectives
5.1
Critical Mass Required + Multidisciplinary Skills
Critical Mass: The identification of factors controlling or enabling the transition of tumours into metastatic
entities requires integrated efforts utilizing tools available in different experimental systems. Our choice to
utilize different developmental model organisms requires the assembly of several expert groups each of which
contributes the expertise in a specific system.
5.2
Proposed Consortium (Organisation, Background and Role)
Organisation
Country
Chief
Area of Excellence
Role in Project
Cell migration in zebrafish
Core group
Scientist
1
Max-Planck-
Germany
Erez Raz
Germany
Carmen
Institute for
Biophysical
Chemistry,
Göttingen
2
Max-Delbrueck-
Birchmeier
Centrum, Berlin
3
Weizmann
Core group
Israel
Talila Volk
Drosophila embryonic
Core group
development
Institute of
Science, Rehovot
4
Instituto Cajal,
Spain
Institute for
Cancer Research
Core group
Nieto
Madrid
5
M. Angela
Italy
Luca
Receptors controlling cell
Tamagnone
motility and invasion
Core group
and Treatment –
University of
Torino
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5.
EOI.FP6.2002
Promotion of Results Outside of the Consortium
Promotion of the results outside of the project will be performed by involving medical experts in the field of
tumour biology and metastasis. Attempts will be made to involve biotech companies in an effort to develop
diagnostic and therapeutical tools.
6.
How the Project will be Managed
A designated co-ordinator will act as the intermediary between participants and the commission. He will
take care of implementing a legal and administrative office in charge of the management of the network. A
core committee will supervise the research activities as well as the establishment of the shared database
where the results will be stored. Bi-annual meeting of the chief scientists and members of the groups will
be conducted to direct the efforts and ensure optimal use of the gathered data.
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