Wnt pathway induced interactions between intestinal crypt stem cells as well as colon cancer cells with their associated mesenchymal niche

• Antragsteller: Professor Dr. Daniel Stange, Ph.D.
• Fachliche Zuordnung: Allgemein- und Viszeralchirurgie
• Förderung: Förderung von 2007 bis 2011
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 44930175

WNT pathway mutations constitute the primary transforming event in colorectal cancer (CRC). The group of Prof. Clevers (Hubrecht Laboratory, Utrecht, The Netherlands) has previously shown that beta-catenin/TCF4 in CRC cells activates a genetic program that is physiologically active in the proliferative compartment of colon crypts, and that the beta catenin/TCF4 complex constitutes the master switch that controls proliferation versus differentiation in healthy and malignant intestinal epithelial cells. The group has more recently performed microarray expression analyses on late embryonic intestines of wildtype and TCF4 -/- knockout mice, which fail to form the crypt progenitor compartments. In addition to the TCF4 target gene program, very significant decreases in genes that are normally expressed in mesenchymal cells directly surrounding the crypts was noted. It thus appears that in the absence of crypt compartments in TCF4 -/- intestines, a mesenchymal crypt stem cell niche is not formed. It is therefore hypothesized that inductive interactions between the crypt and its surroundings create this niche. It is highly likely that WNT pathway induced adenomas (like their physiological equivalents, the crypts) create, and then depend on, a mesenchymal niche. Several mesenchymal candidate genes have already been identified for the crypt stem cell / mesenchymal interaction, in particular Wnt-5a. The specific aims of this research fellowship with Prof. Clevers are 1 to (1) investigate Wnt-5a expression in the niches of colonic adenomas, carinomas and liver metastases, and to (2) investigate the functional role of Wnt5a in the crypt niche by performing in vivo studies of a mutant mouse model. Additionally, we will study the effect of the Wnt5a knockout on early adenomas of APC +/- (“APCmin”) mice. When successful, this study will define novel target genes for therapeutic intervention in (early) intestinal neoplasias.

• DFG-Verfahren: Forschungsstipendien
• Internationaler Bezug: Niederlande
• Gastgeber: Professor Dr. Hans Clevers, Ph.D.