3D Coculture Model of the Brain Parenchyma-Metastasis Interface of Brain Metastasis.

Central nervous system (CNS ) metastasis is not only an increasing but still a very unsatisfying clinical problem, with very few treatment options nowadays and an unmet clinical need. Additionally, the patients suffer from severe neurological symptoms. Furthermore the preclinical studies are limited and thus innovative methods are needed to study the mechanism of CNS metastasis during the final steps. Especially nowadays, the most critical step during metastasis seems to be the contention of the microenvironment of host organs with the cancer cells coming from other organs. More and more data indicate that this contention often leads to apoptosis of the pre-metastatic cells and prevents successful metastasis. However, this important step is barely understood. To further improve our knowledge about this important step of metastasis we developed a new experimental tool where we coculture an organotypic brain slice with a 3D tumor cell plug embedded in Matrigel for 3-4 days.This model especially mimics the interactions of cancer cells and glial cells at the interface of the brain parenchyma and the metastatic tissue. Therefore this coculture method with an organotypic brain slice and a tumor cell plug allows us to visualize and/or manipulate the interactions at this very important zone. Furthermore, it also allows us to use brain tissue from genetically engineered mice and/or genetically modified tumor cells to investigate genes of interest in the microenvironment or in cancer cells. Moreover this method avoids the use of a large number of animals and is especially useful in identifying the invasiveness of different tumor cell lines into the brain parenchyma as well as in studying the effect of specific treatments against brain metastasis progression during the final and most critical steps of metastasis.