PTEN-restoration abrogates brain colonization and perivascular invasion by melanoma cells
Background: Melanoma brain metastases (MBM) continues to be a significant clinical problem with limited treatment options. Highly invasive melanoma cells migrate along the vasculature and perivascular cells may contribute to residual disease and recurrence. PTEN loss and hyperactivation of AKT occur in MBM; however, a role for PTEN/AKT in perivascular invasion has not been described.Methods: We used in vivo intracranial injections of murine melanoma and bulk RNA sequencing of melanoma cells co-cultured with brain endothelial cells (brECs) to investigate brain colonization and perivascular invasion.Results: We found that PTEN-null melanoma cells were highly efficient at colonizing the perivascular niche relative to PTEN-expressing counterparts. PTEN re-expression (PTEN-RE) in melanoma significantly reduced brain colonization and migration along the vasculature. We hypothesized this phenotype was mediated through vascular-induced TGFB secretion, which drives AKT phosphorylation. Disabling TGFB signaling in melanoma cells reduced colonization and perivascular invasion; however, introduction of constitutively-active myristolated-AKT (myrAKT) restored overall tumor size but not perivascular invasion.Conclusions: PTEN loss facilitates perivascular brain colonization and invasion of melanoma. TGFB-AKT signaling partially contributes to this phenotype, but further studies are needed to determine the complementary mechanisms that enable melanoma cells to both survive and spread along the brain vasculature.