Dissecting neural-like cell states in melanoma brain metastasis

Metastatic spread to the brain is common in patients with advanced melanoma, is difficult to treat, and frequently results in the patient's death. Although the importance of brain metastasis is broadly recognized, our understanding of the molecular underpinnings is rudimentary, but may inform novel therapies. In previous work, our groups found that cancer cells giving rise to brain metastasis adopt molecular features that resemble those of normal brain cells, such that they 'speak the same language' as their target organ. We now propose to dissect the mechanisms that underly the ability of these cells to adapt to the brain as a seeding site. For this purpose, we will implement several innovations developed by our groups. Among others, we will leverage new mouse models that more faithfully recapitulate human biology, use novel technical tools that allow us to understand the evolution of brain metastasis at unprecedented resolution, and test a therapeutic strategy that could pave the way for translating this work to patients with melanoma brain metastasis. Together, this work will make major contributions in several ways: first, through the development of novel models to study brain metastasis more broadly; second, by dissecting a fundamental process of how cancer cells adopt to their target organ for metastatic spread; and third, propose a potentially useful therapeutic approach that may selectively prevent or treat existing melanoma brain metastasis.