title: Real-time cell cycle imaging during melanoma growth, invasion, and drug response.
abstract: Solid cancers are composed of heterogeneous zones containing proliferating and quiescent cells. Despite considerable insight into the molecular mechanisms underlying aberrant cell cycle progression, there is limited understanding of the relationship between the cell cycle on the one side, and melanoma cell motility, invasion, and drug sensitivity on the other side. Utilizing the fluorescent ubiquitination-based cell cycle indicator (FUCCI) to longitudinally monitor proliferation and migration of melanoma cells in 3D culture and in vivo, we found that invading melanoma cells cycle actively, while G1-arrested cells showed decreased invasion. Melanoma cells in a hypoxic environment or treated with mitogen-activated protein kinase pathway inhibitors remained G1-arrested for extended periods of time, with proliferation and invasion resuming after re-exposure to a more favorable environment. We challenge the idea that the invasive and proliferative capacity of melanoma cells are mutually exclusive and further demonstrate that a reversibly G1-arrested subpopulation survives in the presence of targeted therapies.
authors.affiliation: The Centenary Institute, Newtown, NSW, Australia; Discipline of Dermatology, University of Sydney, Sydney, NSW, Australia; Department of Dermatology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia; The University of Queensland Diamantina Institute, Translational Research Institute, The University of Queensland, Brisbane, Qld, Australia.
authors.forename: Nikolas K
authors.initials: NK
authors.lastname: Haass
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Beaumont
authors.forename: David S
authors.initials: DS
authors.lastname: Hill
authors.forename: Andrea
authors.initials: A
authors.lastname: Anfosso
authors.forename: Paulus
authors.initials: P
authors.lastname: Mrass
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Munoz
authors.forename: Ichiko
authors.initials: I
authors.lastname: Kinjyo
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry; D016193:G1 Phase; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D025801:Ubiquitin
keywords: cancer drug resistance; fluorescent ubiquitination-based cell cycle indicator; invasion; melanoma heterogeneity; migration; real-time imaging; tumor microenvironment