Metastasis is traditionally viewed as a linear series of discrete events or steps, collectively referred to as the invasion-metastasis cascade. During this process, cancer cells at the primary site of tumor growth dissociate from adjacent cells, partially degrade the underlying basement membrane, and penetrate into the underlying interstitial matrix. Subsequently, as they sculpt a permissive microenvironment, tumor cells foster the development of a tumor vasculature and exploit its discontinuities to gain access to the bloodstream and disseminate through the bloodstream. Finally, upon arresting in the microcirculatory system of the target organ and infiltrating its stroma, cancer cells adopt various strategies to survive and eventually outgrow into macroscopic lesions. The evolution of the cellular attributes that enable individual tumor cells to successfully negotiate the invasion-metastasis cascade is akin to a Darwinian selection process, whereby only a small percentage of the cells that emerge from one step acquire the genetic or epigenetic alterations that enable them to complete the subsequent step.
The Members of the Metastasis Research Institute investigate the genetic and epigenetic changes and the regulatory circuits and transcriptional programs that govern various steps of metastasis, including dissemination, dormancy and reactivation. We place special emphasis on the cell fate changes that facilitate these processes, such as the epithelial-to-mesenchymal transition (EMT) and the reversal of this process (MET) and the reversion of tumor progenitor cells to cancer stem cells and the reversal of this process. Furthermore, we study the drug resistance of cancer stem cells and metastasis-initiating cells and the metabolic rewiring that occurs during dormancy and reactivation. Finally, we aim to develop small molecules and antibody-based therapies targeting metastatic cells with the ultimate goal of using these agents in combination with canonical oncogene-targeted therapies in the adjuvant or therapeutic setting.