Cadherin-mediated cell-cell adhesion regulates collective pediatric glioma cell migration

Pediatric high-grade gliomas are highly invasive and cure rates are low. Tumor cells invade along varied migratory tracks, following neural cell strands or extracellular matrix around blood vessels, resembling neuron progenitors during brain development. In contrast to their adult counterparts, mechanisms that direct invading cells to follow these different routes remain poorly characterized. We found that N-cadherin differentially regulates pediatric high-grade glioma collective migration according to the microenvironment, inhibiting invasion of extracellular matrix but stimulating migration on neurons or astrocytes. Migrating leader cells exhibited faster endocytosis of N-cadherin and β-catenin and increased proliferation and nuclear Yes-associated protein 1 (YAP1) relative to follower cells. YAP1 localization was regulated by cell density, and inhibition of YAP1 and its paralog TAZ decreased N-cadherin internalization and retarded migration. Therefore, feedback between YAP1/TAZ and N-cadherin recycling regulates leader-follower phenotypic identity and differential migration on extracellular matrix and neural substrates.