Aurora kinase A enables collective invasion and metastasis by endowing a leader cell phenotype and stabilizing cohesion with follower cells

Abstract

The metastatic process initiates with collective cell invasion into surrounding tissues and axillary nodes, and subsequent colonization at a distant site. Previously, we found collective invasion is augmented during the G2 cell cycle phase, facilitated through Aurora kinase A (AURKA)-mediated centrosome polarization in the leader cell. Here, we identify cell cycle-associated gene signatures as overrepresented in axilla and liver metastatic sites, with AURKA expression strongly correlated with breast cancer metastasis signatures, and pan-cancer patient survival. Then, we show GFP-AURKA expression endows breast epithelia cells with the ability to form outgrowths within immune-incompetent chicken embryos. Multi-parametric imaging of wound closure assays reveals phenotypes enabled by, and dependent upon AURKA expression. We discover leader cells express AURKA and acquire front-polarized centrosomes, which differentiates them from other cells in the migrating group. Ectopic expression of GFP-AURKA induces a leader cell phenotype. Conversely, inhibition of AURKA activity alters actin dynamics, promotes turnover of cell contacts, and reduces coordination within migrating groups. Specifically, AURKA interacts with the actin regulator EPLIN, and AURKA inhibition localizes EPLIN to lamellipodia and away from E-cadherin-positive contacts. Inhibiting these necessary roles for AURKA may provide a critical barrier against the metastatic spread of human breast carcinoma cells.