Rho/ROCK pathway inhibition by CDK inhibitor p27kip1 participates in the onset of macrophage 3D-mesenchymal migration

Abstract

Macrophage tissue infiltration can promote tumour development. Depending on the extracellular matrix architecture, macrophages can adopt two migration modes: amoeboid (AM), common to all leukocytes; and mesenchymal (MM), restricted to macrophages and certain tumour cells. Here, we investigated the initiating mechanisms involved in macrophage MM. We show that a single macrophage is able to use both migration modes. Macrophage MM is correlated with a decreased Rho/Rho-associated protein kinase (ROCK) activity and potentiated by ROCK inhibition, suggesting that AM inhibition could participate in MM initiating mechanisms. We identify the cyclin-dependent kinase (CDK) inhibitor p27kip1 as a new effector of macrophage 3D-migration. Using p27kip1 siRNA and p27kip1 mutant mice, we show that p27kip1 promotes MM and hinders AM upstream of the Rho/ROCK pathway, a process associated with a relocation of the protein from the nucleus to the cytoplasm. Finally, we observe that cytoplasmic p27kip1 is required for in vivo macrophage tissue infiltration in induced tumours in mice. This study provides the first evidence that silencing of AM through inhibition of the Rho/ROCK pathway by p27kip1 participates in the onset of macrophage MM.