Melanoma cells appropriate pericyte:endothelial cell crosstalk during perivascular invasion in the brain

Post brain colonization, cancer cells may adhere to and spread along the abluminal surface of the vasculature providing advantageous access to oxygen, nutrients, and vessel-derived paracrine factors. For example, brain-tropic melanoma cells are well-known to invade along or within blood vessels at the invasive front, but the molecular mechanisms that guide this process are not well-characterized. We have used melanoma cells of different phenotypic states (melanocytic versus mesenchymal) to characterize different modes of perivascular invasion in the brain. We find that Sox9 hi mesenchymal state melanoma cells undergo pericyte-like spreading along brain blood vessels via a Snail1-dependent process; in contrast, Sox10 hi melanocytic state melanoma form proliferative, perivascular clusters. Snai1 deletion in mesenchymal-state melanoma cells diminishes Tgfβ-induced expression of Pdgfrβ which impairs Tgfβ/Pdgf ligand-driven motility along the brain microvasculature and dramatically reduces perivascular dispersal of melanoma cells throughout the brain post-colonization. These data suggest that, depending on their transcriptional/phenotypic state, some melanoma cells may appropriate signals that typically mediate endothelial cell:pericyte cross talk as an adaptive mechanism for maintaining vessel proximity and motility within the brain microenvironment.