title: Role of dynamin in elongated cell migration in a 3D matrix.
abstract: The use of 3-dimensional (3D) collagen gels has yielded new insights into the migratory behaviour of cancer cells. While the large GTPase dynamin has emerged as an important regulator of cancer cell migration and invasion under 2D conditions, its role in 3D migration is unclear. We have used a potent dynamin modulator, a bis-tyrphostin derivative, Ryngo® 1-23, to investigate the role of dynamin in 3D migration in 3 different cell lines. The compound specifically inhibits persistent, elongated 3D migration in U87MG and SMA-560 cells. Treated U87MG cells adopt a rounded morphology that is not due to apoptosis, loss of matrix metalloprotease activity or inhibition of clathrin-mediated endocytosis. Given that Ryngo 1-23 is known to regulate dynamin oligomerisation and actin dynamics at the leading edge, we analysed actin filament distribution. Ryngo 1-23 induced a switch in actin filament organization in 3D cultures resulting in the generation of multiple short actin-rich microspikes. Correlated with the change in actin filament distribution, cells displayed reduced collagen gel contraction. Since acto-myosin force transmission to the extra-cellular matrix underpins persistent, elongated migration, our results suggest that Ryngo 1-23 modulates this process in 3D migration via dynamin-mediated regulation of acto-myosin force transmission to the extra-cellular matrix.
authors.affiliation: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
authors.forename: Justin G
authors.initials: JG
authors.lastname: Lees
authors.affiliation: Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales, Australia.
authors.forename: Nick N
authors.initials: NN
authors.lastname: Gorgani
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Alaina J
authors.initials: AJ
authors.lastname: Ammit
authors.affiliation: Faculty of Chemistry, School of Environmental and Life Sciences, The University of Newcastle, Callaghan, New South Wales, Australia.
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
authors.affiliation: Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales, Australia.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.affiliation: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Westmead, New South Wales, Australia; Discipline of Paediatrics and Child Health, The University of Sydney, Sydney, New South Wales, Australia. Electronic address: geraldine.oneill@health.nsw.gov.au.
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000737:chemistry; D003373:Coumaric Acids / Q000494:pharmacology; D003487:Cyanoacrylates / Q000494:pharmacology; D034281:Dynamins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005782:Gels; D006801:Humans; D021621:Imaging, Three-Dimensional; D051381:Rats; D054457:Tissue Scaffolds; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: C000600733:Bis-T-23 compound; D003373:Coumaric Acids; D003487:Cyanoacrylates; D005782:Gels; C000601112:Ryngo 1-23; D020032:Tyrphostins; D003094:Collagen; D034281:Dynamins
keywords: 3D matrix; Cancer biology; Cell migration; Dynamin; Invasion