Principal Investigator Robert Weinberg
The intracellular regulatory circuitry that programs the epithelial-mesenchymal transition involves the actions of a series of transcription factors that induce expression of one another. Each of these transcription factors can act in a pleiotropic fashion to choreograph an EMT, but seems to collaborate with others in various epithelial cell types to organize this program and ensure that a large coterie of downstream effectors can collaborate to push cells into an epithelial/stem-cell state.
Having learned many of the requirements for creating primary human tumors, we would like to determine the nature of some of the genetic elements that lead to the formation of invasive and ultimately metastatic tumor cells. Using expression arrays, we have identified two transcription factors, Twist and Mesenchyme Forkhead (also known as FOXC2) , which appear to play key roles in programming many of the phenotypes of invasive cells. Embryology reveals the identity of a third factor, termed Goosecoid, which appears capable of programming the epithelial-mesenchymal transition both during early embryogenesis and during the invasive stages of certain carcinomas. A fourth factor, termed Slug, may contribute to the invasive phenotype of yet other tumors. Acting alone or in combination, these factors may be able to program many of the phenotypes associated with invasive and metastatic cells. In addition, we are examining the last stage of the invasion-metastasis cascade, in order to determine how disseminated cancer cells are able to adapt to a novel tissue environment and colonize this environment, yielding a macroscopic metastasis.