Phagocytic glioblastoma-associated microglia and macrophages populate invading pseudopalisades

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Abstract
Hypoxic pseudopalisades are a pathological hallmark of human glioblastoma, which is linked to tumor malignancy and aggressiveness. Yet, their function and role in the tumor development has scarcely been explored. It is thought that pseudopalisades are formed by malignant cells escaping from the hypoxic environment, although evidence of the immune component of pseudopalisades has been elusive. In the present work, we analyze the immunological constituent of hypoxic pseudopalisades using high-resolution three-dimensional confocal imaging in tissue blocks from excised tumors of glioblastoma patients, and mimic the hypoxic gradient in microfluidic platforms in vitro to understand the cellular motility. We visualize that glioblastoma-associated microglia and macrophages abundantly populate pseudopalisades, displaying an elongated kinetic morphology across the pseudopalisades, and are oriented towards the necrotic focus. In vitro experiments demonstrate that under hypoxic gradient, microglia show a particular motile behavior characterized by the increase of cellular persistence in contrast with glioma cells. Importantly, we show that glioblastoma-associated microglia and macrophages utilize fibers of glioma cells as a haptotactic cue to navigate along the anisotropic structure of the pseudopalisades and display a high phagocytic activity at the necrotic border of the pseudopalisades. In this study, we demonstrate that glioblastoma-associated microglia and macrophages are the main immune cells of pseudopalisades in glioblastoma, traveling to necrotic areas to clear the resulting components of the protrombotic milieu, suggesting that the scavenging features of glioblastoma-associated microglia and macrophages at the pseudopalisades serve as an essential counterpart for glioma cell invasion.
Funding Information
  • Spanish Ministry of Economy and Competitiveness
  • European Regional Development Fund
  • Spanish Ministry of Science, Innovation and Universities

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