Metastasis as a faulty recapitulation of ontogeny

RAF oncogenes are involved in a variety of phenotypic switch phenomena. If for example oncogenic RAF is expressed together with Myc in B lineage cells, a lineage switch to macrophages occurs at low frequency in vitro and in vivo. In addition, if RAF is expressed in type II alveolar epithelial cells slow growing lung adenomas are formed and a switch from columnar to cuboidal cells is detected in these mice upon p53 deletion. A similar switch is also seen, if ectopic Myc is present in our lung tumor mouse model. Moreover, in the liver of these mice with both oncogenes metastases are found. If E-cadherin function is impaired in our RAF-dependent lung tumor model, a switch from adenoma to adenocarcinoma occurs and genes characteristic for the early endodermal lineage are expressed. Based on these data I propose a novel model of metastasis and describe its implications. The hallmark of the model is the induction of a state of plasticity in tumor cells, which allows the reversal of differentiation to an earlier point in their ontogenic history