title: FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis.
abstract: Cell migration in confined 3D tissue microenvironments is critical for both normal physiological functions and dissemination of tumor cells. We discovered a cytoskeletal structure that prevents damage to the nucleus during migration in confined microenvironments. The formin-family actin filament nucleator FMN2 associates with and generates a perinuclear actin/focal adhesion (FA) system that is distinct from previously characterized actin/FA structures. This system controls nuclear shape and positioning in cells migrating on 2D surfaces. In confined 3D microenvironments, FMN2 promotes cell survival by limiting nuclear envelope damage and DNA double-strand breaks. We found that FMN2 is upregulated in human melanomas and showed that disruption of FMN2 in mouse melanoma cells inhibits their extravasation and metastasis to the lung. Our results indicate a critical role for FMN2 in generating a perinuclear actin/FA system that protects the nucleus and DNA from damage to promote cell survival during confined migration and thus promote cancer metastasis.
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Colleen T
authors.initials: CT
authors.lastname: Skau
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Fischer
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Pinar
authors.initials: P
authors.lastname: Gurel
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Institut Curie, CNRS UMR 144, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Hawa Racine
authors.initials: HR
authors.lastname: Thiam
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Tubbs
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA; Magnet Lab, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Baird
authors.affiliation: Magnet Lab, Florida State University, Tallahassee, FL 32306, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Davidson
authors.affiliation: Institut Curie, CNRS UMR 144, 26 rue d'Ulm, 75005 Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Piel
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Alushin
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Andre
authors.initials: A
authors.lastname: Nussenzweig
authors.affiliation: Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Steeg
authors.affiliation: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: watermancm@nhlbi.nih.gov.
authors.forename: Clare M
authors.initials: CM
authors.lastname: Waterman
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004622:Embryo, Mammalian / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions; D000080865:Formins; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary*; D008545:Melanoma / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism*; D009362:Neoplasm Metastasis; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; C587953:Fmn2 protein, human; D000080865:Formins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C549436:formin 2 protein, mouse
keywords: DNA damage; actin; cell migration; confined migration; focal adhesion; formin; melanoma; metastasis; stress fiber; ventral actin bundle