Molecular analysis of intestinal stem cell associated genes in colorectal cancer (CRC)

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An integrated molecular profiling effort compared primary colorectal tumors with liver metastases from the same patient and revealed genes and pathways that are differentially regulated in the process of metastasis. Another set of important candidate genes was derived from the identification of genes activated in CD133-positive colorectal tumor cells, which are considered to represent a cellular fraction enriched in cancer stem cells. The aim of this project is to functionally characterize these two sets of candidate genes in order to elucidate their role in colorectal carcinogenesis and the process of metastasis. Candidate gene expression will be modulated in normal and colorectal cell lines and phenotypic effects will be investigated by applying assays which test cell adhesion, cell migration and Invasion. Expression and DNA methylation profiling upon gene modulation will allow the generation of a systematic view of the molecular pathways and networks involved in metastasis-related processes initiated by our candidate genes. Following the concept of cancer stem cells äs the founding cells of metastases, the effect of top-ranked genes and members from the two top-ranked pathways will be analyzed in depth using spheroid cultures. Work using this prime in vitro System and xenotransplant models will be performed in close collaboration with subproject 3 and other subprojects. Furthermore, we will screen for novel inhibitors using biologically active fungi extracts and/or the small molecular screening facility (established between the EMBL and the DKFZ). The testing of these inhibitors in the cellular Systems with metastasis-related phenotype, which are developed in the course of this subproject, will allow validation of newly emerging molecular interference strategies.