title: Oncogenic BRAF-Mediated Melanoma Cell Invasion.
abstract: 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.
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Hezhe
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Shujing
authors.initials: S
authors.lastname: Liu
authors.affiliation: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Gao
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 770303, USA.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Yueyao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 770303, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Miller
authors.affiliation: Department of Biology, Drexel University, Philadelphia, PA 19104, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wenqun
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Wu
authors.affiliation: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Clemens
authors.initials: C
authors.lastname: Krepler
authors.affiliation: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Sproesser
authors.affiliation: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xiao
authors.affiliation: Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Giorgos C
authors.initials: GC
authors.lastname: Karakousis
authors.affiliation: Abramson Cancer Center and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Field
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
authors.affiliation: Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: xug@mail.med.upenn.edu.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: guowei@sas.upenn.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D022081:Cell Surface Extensions / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005818:Genetic Engineering; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology*; D033921:Vesicular Transport Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D051356:Cortactin; C547754:EXOC7 protein, human; D033921:Vesicular Transport Proteins; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: invadopodia; oncogenic BRAF; tumor invasion