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

Abstract

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 Sox9hi mesenchymal state melanoma cells undergo pericyte-like spreading along brain blood vessels via a Snail1-dependent process; in contrast, Sox10hi 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 in the brain microenvironment.

Advancements in melanoma cancer metastasis models

“…For the study of melanoma brain metastasis, fluorescent‐labeled melanoma cells can be transplanted or seeded onto murine or rat hippocampus slices to examine their proliferation, migration, and invasion potential. Brain slices have also been used to investigate the role of astrocytes in facilitating melanoma brain tropism and metastasis as well as to study the role of genes in the regulation of migration and invasion of melanoma cells (Doron et al, 2019; Hegerfeldt et al, 2002; Murry et al, 2006; Schwartz et al, 2016; Zhang et al, 2022). Organotypic tissue slices allow for the study of biomechanical properties of organs (e.g., stiffness or cell adhesion) and analysis of treatment responses in an intact organ environment (Doron et al, 2019; Holsken et al, 2006; Murry et al, 2006; Radke et al, 2017; Zhu et al, 2022).…”