The Wnt and Hedgehog signaling pathways play critical roles during embryonic development and in adults through modulation of proliferation, cell migration and differentiation. Inappropriate activation of these pathways through mutations in resident stem cells can lead to tumor development in tissue such as the gastrointestinal tract or the skin. Targeting these oncogenic pathways or the stem cells compartment driving the tumorigenic process represent therapeutic opportunities for the treatment of these tumor types. To explore the potential of such approach in colorectal cancer, we have developed an orthotopic model of colorectal cancer. Introduction of intestinal organoids with increasing number of mutations lead to a corresponding increase in tumor growth rate and to spontaneous metastatic dissemination to the liver and lung. This approach enabled us to study of each step of the metastatic process as well as the testing of therapeutic modalities. We also uncovered that cell plasticity involved in tissue repair and regeneration poses new challenges for the efficacy of these therapeutic approaches in cancer.