Constitutive activation of the Wnt pathway is the key step for initiation of colorectal cancer (CRC). Wnt signaling also plays an essential role in the maintenance of intestinal stem cells (ISCs). In addition, acquisition of a constitutive crypt stem/progenitor phenotype represents the first step towards malignancy. The identification of the Wnt target gene Lgr5 as a marker for ISCs and the finding that Lgr5+ ISCs represent the origin of intestinal cancer suggest that specific features of ISC are required to initiate CRC. Given the critical role of ISCs in CRC onset, we intend to study their contribution to CRC progression, tumor recurrence, and metastasis. Characterization of Lgr5+ CRC cells at different disease stages will clarify, which part of the “stemness” genetical program remains conserved during progression of malignancy. We will also address to which extent an Lgr5+ CRC cell residing in a primary tumor or in metastasis resembles a crypt Lgr5+ ISC. To achieve this, progression of intestinal cancer derived from ISCs or differentiated cells will be studied using a novel transgenic mouse model system: Starting from defined, targeted cells which have acquired Wnt activation combined with mutation in KRAS, tumor progression can be tracked by fluorescent proteins concomitantly induced with compound mutations. “State-of the art” flow-cytometry-based sorting techniques will be used to isolate different tumor sub-populations in order to characterize them in detail. Interestingly, only a rare sub-population of tumor cells in CRC patients, so-called “cancer stem cells” (CSCs), is able to re-establish tumor growth in immune-deficient animals. We seek to understand how these tumor-promoting cells are genetically and functionally related to Lgr5+ ISC and Lgr5+ cells in CRC. Our results will achieve significant advancement in understanding the relationship between CSCs and ISCs and hold potential for the future development of both therapeutic and diagnostic tools.