ADAM12 induction by TWIST1 promotes tumor invasion and metastasis via regulation of invadopodia and focal adhesions

Abstract

The Twist1 transcription factor promotes tumor invasion and metastasis by inducing Epithelial-Mesenchymal Transition (EMT) and invadopodia-mediated extracellular matrix degradation. The critical transcription targets of Twist1 in mediating these events remain to be uncovered. Here, we report that Twist1 strongly induces expression of a disintegrin and metalloprotease 12 (ADAM12). Expression levels of Twist1 and ADAM12 are tightly correlated in human breast tumors. Knocking down ADAM12 blocked cell invasion in the 3D mammary organoid culture. Suppression of ADAM12 also inhibited Twist1-induced tumor invasion and metastasis in human breast tumor xenografts without affecting primary tumor formation. Mechanistically, knockdown of ADAM12 in breast cancer cells significantly decreased invadopodia formation and matrix degradation and simultaneously increased overall cell adhesion to the ECM. Live-imaging analysis shows that knockdown of ADAM12 significantly inhibited focal adhesion turnover. Mechanistically, both the disintegrin and metalloprotease domains of ADAM12 are required for its proper function at invadopodia, while the metalloprotease domain is dispensable for its function at focal adhesions. Together, these data suggest that ADAM12 plays a critical role in tumor invasion and metastasis by regulating both invadopodia and focal adhesions.