EphA2 cleavage helps tumor cells go it alone

Amatrix metalloproteinase promotes the invasion of individual cancer cells by cleaving the receptor tyrosine kinase EphA2, Sugiyama et al. show.

Tumor cells can invade surrounding tissues as a group or as single cells that adopt either a rounded, amoeboid shape or an elongated, “mesenchymal” morphology. The EphA2 receptor promotes cancer cell invasion, though how it does this is unclear because tumors with high EphA2 levels often show reduced expression of the corresponding ligand, ephrinA1. EphA2 up-regulates MT1-MMP, a membrane-bound protease that promotes collective and mesenchymal invasion by degrading the extracellular matrix. Sugiyama et al. found that MT1-MMP then binds and cleaves EphA2 in certain breast cancer cell lines, boosting their ability to invade as single, rounded cells.

MT1-MMP cleaved EphA2 at the cell surface, triggering the receptor’s internalization. Once inside the cell, EphA2 activated the small GTPase RhoA to enhance cellular contractility and repulsion, prompting cells to round up and detach from their neighbors. Cells expressing a cleavage-resistant form of EphA2 tended to invade as a group, whereas a cleavage-sensitive mutant promoted the dissemination of single cells from tumors formed in mice.

EphA2 and MT1-MMP were often coexpressed in human tumor samples, suggesting that this pathway may operate in vivo to determine how cancer cells invade their surroundings. Senior author Kaisa Lehti now wants to investigate why and how intra-cellular EphA2 activates RhoA and rounded, single-cell invasion, whereas uncleaved, cell-surface EphA2 stimulates the invasive growth of more coherent cell colonies.