P120-catenin dependent collective brain infiltration by glioma cell networks

Abstract

Diffuse brain infiltration by glioma cells causes detrimental disease progression, however its multicellular coordination is poorly understood. We here show that glioma cells infiltrate brain collectively, as multicellular networks. Contacts between moving glioma cells were adaptive epithelial-like or filamentous junctions stabilized by N-cadherin, β-catenin and p120-catenin, which underwent kinetic turn-over, transmitted intercellular calcium transients and mediated directional persistence. Downregulation of p120-catenin compromised cell-cell interaction and communication, disrupted collective networks, and both the cadherin and RhoA binding domains of p120-catenin were required for network formation and migration. Deregulating p120-catenin further prevented diffuse glioma cell infiltration of the mouse brain with marginalized microlesions as outcome. Transcriptomics analysis identified p120-catenin as upstream regulator of neurogenesis and cell cycle pathways and predictor of poor clinical outcome in glioma patients. Collective glioma networks infiltrating the brain thus depend on adherens junctions dynamics the targeting of which may offer an unanticipated strategy to halt glioma progression.