title: Lamellipodin promotes invasive 3D cancer cell migration via regulated interactions with Ena/VASP and SCAR/WAVE.
abstract: Cancer invasion is a hallmark of metastasis. The mesenchymal mode of cancer cell invasion is mediated by elongated membrane protrusions driven by the assembly of branched F-actin networks. How deregulation of actin regulators promotes cancer cell invasion is still enigmatic. We report that increased expression and membrane localization of the actin regulator Lamellipodin correlate with reduced metastasis-free survival and poor prognosis in breast cancer patients. In agreement, we find that Lamellipodin depletion reduced lung metastasis in an orthotopic mouse breast cancer model. Invasive 3D cancer cell migration as well as invadopodia formation and matrix degradation was impaired upon Lamellipodin depletion. Mechanistically, we show that Lamellipodin promotes invasive 3D cancer cell migration via both actin-elongating Ena/VASP proteins and the Scar/WAVE complex, which stimulates actin branching. In contrast, Lamellipodin interaction with Scar/WAVE but not with Ena/VASP is required for random 2D cell migration. We identified a phosphorylation-dependent mechanism that regulates selective recruitment of these effectors to Lamellipodin: Abl-mediated Lamellipodin phosphorylation promotes its association with both Scar/WAVE and Ena/VASP, whereas Src-dependent phosphorylation enhances binding to Scar/WAVE but not to Ena/VASP. Through these selective, regulated interactions Lamellipodin mediates directional sensing of epidermal growth factor (EGF) gradients and invasive 3D migration of breast cancer cells. Our findings imply that increased Lamellipodin levels enhance Ena/VASP and Scar/WAVE activities at the plasma membrane to promote 3D invasion and metastasis.
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Carmona
authors.affiliation: King's College London, Randall Division of Cell and Molecular Biophysics, London, UK.
authors.forename: U
authors.initials: U
authors.lastname: Perera
authors.affiliation: King's College London, Research Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Gillett
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Naba
authors.affiliation: King's College London, Randall Division of Cell and Molecular Biophysics, London, UK.
authors.forename: A-L
authors.initials: AL
authors.lastname: Law
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.|Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: V P
authors.initials: VP
authors.lastname: Sharma
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wyckoff
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Balsamo
authors.affiliation: King's College London, Randall Division of Cell and Molecular Biophysics, London, UK.
authors.forename: F
authors.initials: F
authors.lastname: Mosis
authors.affiliation: King's College London, Division of Cancer Studies, Cancer Epidemiology Group, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: De Piano
authors.affiliation: King's College London, Randall Division of Cell and Molecular Biophysics, London, UK.|King's College London, Research Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, London, UK.|King's College London, Division of Cancer Studies, Richard Dimbleby Department of Cancer Research, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Monypenny
authors.affiliation: King's College London, Research Oncology, Division of Cancer Studies, Faculty of Life Sciences and Medicine, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Woodman
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: McConnell
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mouneimne
authors.affiliation: King's College London, Division of Cancer Studies, Cancer Epidemiology Group, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Van Hemelrijck
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY, USA.|Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Condeelis
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.|Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: R O
authors.initials: RO
authors.lastname: Hynes
authors.affiliation: Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: F B
authors.initials: FB
authors.lastname: Gertler
authors.affiliation: King's College London, Randall Division of Cell and Molecular Biophysics, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: Krause
mesh_terms: D008841:Actin Cytoskeleton / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000235:genetics; D006801:Humans; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D010766:Phosphorylation; D060066:Protein Interaction Maps / Q000235:genetics; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C092744:ENA-VASP proteins; D008565:Membrane Proteins; C493339:RAPH1 protein, human; C495774:Wasf1 protein, mouse; D051300:Wiskott-Aldrich Syndrome Protein Family; D004815:Epidermal Growth Factor