title: Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901.
abstract: Dispersal of glioblastoma (GBM) cells leads to recurrence and poor prognosis. Accordingly, molecular pathways involved in dispersal are potential therapeutic targets. The mitogen activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway is commonly dysregulated in GBM, and targeting this pathway with MEK inhibitors has proven effective in controlling tumor growth. Since this pathway also regulates ECM remodeling and actin organization - processes crucial to cell adhesion, substrate attachment, and cell motility - the aim of this study was to determine whether inhibiting this pathway could also impede dispersal.
  
  
  
  A variety of methods were used to quantify the effects of the MEK inhibitor, PD0325901, on potential regulators of dispersal. Cohesion, stiffness and viscosity were quantified using a method based on ellipsoid relaxation after removal of a deforming external force. Attachment strength, cell motility, spheroid dispersal velocity, and 3D growth rate were quantified using previously described methods.
  
  
  
  We show that PD0325901 significantly increases aggregate cohesion, stiffness, and viscosity but only when tumor cells have access to high concentrations of fibronectin. Treatment also results in reorganization of actin from cortical into stress fibers, in both 2D and 3D culture. Moreover, drug treatment localized pFAK at sites of cell-substratum adhesion. Collectively, these changes resulted in increased strength of substrate attachment and decreased motility, a decrease in aggregate dispersal velocity, and in a marked decrease in growth rate of both 2D and 3D cultures.
  
  
  
  Inhibition of the MAPK/ERK pathway by PD0325901 may be an effective therapy for reducing dispersal and growth of GBM cells.
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Shannon
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Dongxuan
authors.initials: D
authors.lastname: Jia
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Entersz
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Beelen
authors.affiliation: Rutgers-Department of Mechanical and Aerospace Engineering, 98 Brett Rd, Piscataway Township, NJ, 08854, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Carcione
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carcione
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Aria
authors.initials: A
authors.lastname: Mahtabfar
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Connan
authors.initials: C
authors.lastname: Vaca
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Weaver
authors.affiliation: Rutgers-Department of Biomedical Engineering, 599 Taylor Road, Piscataway, NJ, 08854, USA.
authors.forename: David
authors.initials: D
authors.lastname: Shreiber
authors.affiliation: Rutgers-Department of Biomedical Engineering, 599 Taylor Road, Piscataway, NJ, 08854, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Zahn
authors.affiliation: Rutgers-Department of Mechanical and Aerospace Engineering, 98 Brett Rd, Piscataway Township, NJ, 08854, USA.|Rutgers-Department of Mathematics, 110 Frelinghuysen Rd, Piscataway, NJ, 08854, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.affiliation: Rutgers-Department of Mechanical and Aerospace Engineering, 98 Brett Rd, Piscataway Township, NJ, 08854, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA. fotyra@rwjms.rutgers.edu.
authors.forename: Ramsey A
authors.initials: RA
authors.lastname: Foty
mesh_terms: D000199:Actins / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018613:Microscopy, Confocal; D010766:Phosphorylation / Q000187:drug effects; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism
chemical_list: D000199:Actins; D001549:Benzamides; C506614:mirdametinib; D004159:Diphenylamine; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: 3D spheroids; Dispersal velocity; Fibronectin matrix; Glioblastoma; MEK inhibitor