Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
Shujing Liu
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Gao Zhang
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Lawrence N. Kwong
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 770303, USA
Yueyao Zhu
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
John P. Miller
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 770303, USA
Yi Hu
Department of Biology, Drexel University, Philadelphia, PA 19104, USA
Wenqun Zhong
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
Jingwen Zeng
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
Lawrence Wu
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Clemens Krepler
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Katrin Sproesser
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Min Xiao
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Wei Xu
Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Giorgos C. Karakousis
Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
Lynn M. Schuchter
Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Jeffery Field
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Paul J. Zhang
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Meenhard Herlyn
Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA
Xiaowei Xu
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Wei Guo
Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA
Melanoma patients with oncogenic BRAFV600E mutation have poor prognoses. While the role of BRAFV600E 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 BRAFV600E 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 BRAFV600E blocks melanoma cell invasion. In a BRAFV600E-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 BRAFV600E inhibition. Mechanistically, BRAFV600E 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 BRAFV600E in metastasis and suggest that inhibiting invasion is a potential therapeutic strategy against melanoma.
