GUT STEM CELL NICHE · TCF4 target gene program and mesenchymal niche in intestinal crypts and colon cancer

Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.

Накратко на български

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

• HUBRECHT LABORATORY, NETHERLANDS INSTITUTE FOR DEVELOPMENTAL BIOLOGY OF THE ROYAL NETHERLANDS ACADEMY OF ARTS AND SCIENCES (KNAW) · UTRECHTКоординаторНиво градНидерландия

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