Functional analysis of pathways mediating intestinal stem cell plasticity

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In intestinal cancer, Lgr5 expressing intestinal stem cells comprise the cells of origin. Activating mutations in the Wnt pathway have to occur in these cells for a tumor to develop thus underscoring the concept of hierarchical organization of a tumor. We recently obtained evidence that cell plasticity can occur in this hierarchical organization. Enhanced Wnt signaling allows dedifferentiation of post-mitotic epithelial cells and reacquisition of stem cell genes. Once these cells re-express stem cell markers, they are capable of initiating tumorigenesis. Cancer stem like cells (CSLC) are considered essential for tumor maintenance. Moreover, CSLC have been shown to be resistant to chemo- and radiotherapy. Therefore, concepts aiming to eliminate CSLC hold great promise for the therapy of CRC. However, we found that elimination of Lgr5+ cells does not lead to tumor regression and we have identified a compensatory pathway that is responsible for tumor maintenance upon Lgr5+ cell depletion. Moreover, we found that Lgr5+ cells can be replenished after their elimination by other tumor cells. The aim of this project is to identify the cellular and molecular mechanism involved in dedifferentiation of Lgr5- cells in established tumors.