The brain is a highly specialized organ governing vital and cognitive functions. When affected by any injury or disease the brain microenvironment reacts. This also applies to brain metastasis. When metastatic cells reach this organ, they induce a strong defensive response from glial cells. Besides their important role in brain homeostasis, both astrocytes and microglia are the main line of defense that gets activated upon brain damage in multiple neurological disorders. Evidence suggests that this defensive response initially limits the colonization of cancer cells, even when they have completed extravasation through the blood-brain barrier. In fact, in experimental models of brain metastasis more than 90% of cancer cells arriving to this organ perish and never take over. This gives a rationale for the high inefficiency of the metastatic cascade especially during the last steps: the colonization of secondary organs. However, a reduced population of metastatic cells eventually overcome these obstacles and develops into macrometastasis, which will be finally responsible for the fatal consequences in cancer patients. Remarkably, at this late stage of the disease interactions with glial components still remains, which suggest that brain metastatic cells could have remodeled the microenvironment through the course of the disease. In order to define the nature of the reactive brain microenvironment we are interrogating glial cell populations during different stages of metastatic colonization. The main aim of this project is to understand the biology of the reactive microenvironment in brain metastasis to evaluate possible ways to exploit it in future therapeutic pipelines.