title: Drosophila homologue of Diaphanous 1 (DIAPH1) controls the metastatic potential of colon cancer cells by regulating microtubule-dependent adhesion.
abstract: Drosophila homologue of Diaphanous 1 (DIAPH1) regulates actin polymerization and microtubule (MT) stabilization upon stimulation with lysophosphatidic acid (LPA). Recently, we showed strongly reduced lung metastasis of DIAPH1-depleted colon cancer cells but we found accumulations of DIAPH1-depleted cells in bone marrow. Here, we analyzed possible organ- or tissue-specific metastasis of DIAPH1-depleted HCT-116 cells. Our data confirmed that depletion of DIAPH1 strongly inhibited lung metastasis and revealed that, in contrast to control cells, DIAPH1-depleted cells did not form metastases in further organs. Detailed mechanistic analysis on cells that were not stimulated with LPA to activate the cytoskeleton-modulating activity of DIAPH1, revealed that even under basal conditions DIAPH1 was essential for cellular adhesion to collagen. In non-stimulated cells DIAPH1 did not control actin dynamics but, interestingly, was essential for stabilization of microtubules (MTs). Additionally, DIAPH1 controlled directed vesicle trafficking and with this, local clustering of the adhesion protein integrin-β1 at the plasma membrane. Therefore, we conclude that under non-stimulating conditions DIAPH1 controls cellular adhesion by stabilizing MTs required for local clustering of integrin-β1 at the plasma membrane. Thus, blockade of DIAPH1-tubulin interaction may be a promising approach to inhibit one of the earliest steps in the metastatic cascade of colon cancer.
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.|Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Yuan-Na
authors.initials: YN
authors.lastname: Lin
authors.affiliation: Institute for Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ridhirama
authors.initials: R
authors.lastname: Bhuwania
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kira
authors.initials: K
authors.lastname: Gromova
authors.affiliation: Microscopy Imaging Facility, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Antonio Virgilio
authors.initials: AV
authors.lastname: Failla
authors.affiliation: Department of Anatomy and Experimental Morphology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Lange
authors.affiliation: Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Riecken
authors.affiliation: Institute for Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Linder
authors.affiliation: Department of Molecular Neurogenetics, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kneussel
authors.affiliation: Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jakob R
authors.initials: JR
authors.lastname: Izbicki
authors.affiliation: Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Windhorst
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000080865:Formins; D045325:HCT116 Cells; D057809:HEK293 Cells; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D009362:Neoplasm Metastasis; D034622:RNA Interference; D059008:Time-Lapse Imaging; D014183:Transplantation, Heterologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins; D019012:Integrin beta1; D008246:Lysophospholipids; C032881:lysophosphatidic acid
keywords: cellular adhesion; colon cancer; cytoskeleton; formins; metastasis