Objective
The canonical Wnt pathway plays an essential role in the establishment of colon cancer. The mutations implicated in tumour transformation lead to stabilization of beta-catenin, inducing constitutive activity of the pathway. TCF4 is a transcription factor activated downstream of Wnt.
Beta-catenin/TCF4 has been shown by Clevers and colleagues to activate a genetic program in colorectal cancer (CRC) cell-lines, which inhibits differentiation and imposes a crypt progenitor phenotype to these cells. This genetic program is also active in the proliferative compartment of the colon crypts, controlling the switch between proliferation vs. differentiation.
The Clevers lab has also shown that Tcf4 -/- mice fail to maintain a proliferating stem cell compartment in the crypts. A pilot-DNA array analysis of late embryonic intestine has shown that mesenchymal cells surrounding the crypts of Tcf4 -/- mice have decreased expression in some genes. Thus, the absence of crypt formation in Tcf4 -/- mice may in turn induce defects in the surrounding mesenchymal cells. The canonical Wnt pathway likely plays a crucial initiating role in epithelial-mesenchymal interactions to shape the crypt as well as the surrounding mesenchymal cells to create a crypt stem cell niche. Since adenomas arise at the crypt-villus border, similar interactions may be implicated in adenoma formation.
In this proposal we aim to:
1) Identify TCF4 target genes expressed in the crypt epithelial cells affecting mesenchymal cells;
2) Functionally define the signalling molecules and the mesenchymal genes that build the crypt niche;
3) Investigate the relevance of such niches in adenoma formation.
DNA array analyses from CRC cell-lines and in vivo approaches will permit a selection of candidate genes. By using transgenesis/knock-out technologies we will be able to establish the relevance of these selected genes for the mesenchymal crypt-interaction in development of intestinal crypt and adenomas.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- medical and health sciences medical biotechnology cells technologies stem cells
- medical and health sciences clinical medicine oncology colorectal cancer
- natural sciences biological sciences genetics mutation
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2002-MOBILITY-5
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
UTRECHT
Netherlands
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.