Oncogenic BRAF-Mediated Melanoma Cell Invasion

Melanoma patients with oncogenic BRAF^V600E mutation have poor prognoses. While the role of BRAF^V600E in tumorigenesis is well established, its involvement in metastasis that is clinically observed in melanoma patients remains a topic of debate. Here, we show that BRAF^V600E melanoma cells have extensive invasion activity as assayed by the generation of F-actin and cortactin foci that mediate membrane protrusion, and degradation of the extracellular matrix (ECM). Inhibition of BRAF^V600E blocks melanoma cell invasion. In a BRAF^V600E-driven murine melanoma model or in patients' tumor biopsies, cortactin foci decrease upon inhibitor treatment. In addition, genome-wide expression analysis shows that a number of invadopodia-related genes are downregulated after BRAF^V600E inhibition. Mechanistically, BRAF^V600E induces phosphorylation of cortactin and the exocyst subunit Exo70 through ERK, which regulates actin dynamics and matrix metalloprotease secretion, respectively. Our results provide support for the role of BRAF^V600E in metastasis and suggest that inhibiting invasion is a potential therapeutic strategy against melanoma.