Centrosome amplification promotes cell invasion via cell–cell contact disruption and Rap-1 activation

Abstract

Centrosome amplification (CA) is a prominent feature of human cancers linked to tumourigenesis in vivo. Here, we report mechanistic contributions of CA induction alone to tumour architecture and extracellular matrix (ECM) remodelling. CA induction in non-tumourigenic breast cells MCF10A causes cell migration and invasion, with underlying disruption of epithelial cell-cell junction integrity and dysregulation of expression and subcellular localisation of cell junction proteins. CA also elevates expression of integrin β-3, binding partner fibronectin-1, matrix metalloprotease enzymes promoting cell-ECM attachment, ECM degradation, and a migratory and invasive cell phenotype. Using a Chicken Embryo xenograft model for in vivo validation, we show that +CA MCF10A cells invade into the chick mesodermal layer, with inflammatory cell infiltration and marked focal reactions between chorioallantoic membrane and cell graft. We also demonstrate a key role of small GTPase Rap-1 signalling through inhibition using GGTI-298, which blocked various CA-induced effects. These insights reveal that in normal cells, CA induction alone (without additional pro-tumorigenic alterations) is sufficient to confer early pro-tumourigenic changes within days, acting through Rap-1-dependent signalling to alter cell-cell contacts and ECM disruption.