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Updated: Mar 7, 2026
A Rapid Screening Workflow to Identify Potential Combination Therapy for GBM using Patient-Derived Glioma Stem Cells
Published on: March 28, 2021
Inhibition of glioblastoma dispersal by the MEK inhibitor PD0325901
Stephen Shannon1, Dongxuan Jia1, Ildiko Entersz1
1Department of Surgery-Rutgers Robert Wood Johnson Medical School, Clinical Academic Building, 125 Paterson Street, New Brunswick, NJ, 08901, USA.
Background:
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.
Methods:
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.
Results:
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.
Conclusions:
Inhibition of the MAPK/ERK pathway by PD0325901 may be an effective therapy for reducing dispersal and growth of GBM cells.
Insights
Targeting the MAPK/ERK pathway with MEK inhibitors like PD0325901 can reduce glioblastoma (GBM) cell dispersal and growth. This therapy increases cell cohesion and attachment, while decreasing motility, offering a potential treatment for GBM recurrence.
Area of Science:
- Neuro-oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Glioblastoma (GBM) cell dispersal is a key factor in tumor recurrence and poor patient outcomes.
- The mitogen activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway is frequently dysregulated in GBM and is a target for cancer therapies.
- This pathway influences extracellular matrix remodeling and actin organization, processes vital for cell motility and adhesion.
Purpose of the Study:
- To investigate the effect of inhibiting the MAPK/ERK pathway on glioblastoma cell dispersal.
- To determine if MEK inhibitors can impede GBM cell adhesion, motility, and overall growth.
Main Methods:
- Quantification of aggregate cohesion, stiffness, and viscosity using ellipsoid relaxation.
- Assessment of attachment strength, cell motility, spheroid dispersal velocity, and 3D growth rates.
- Utilized the MEK inhibitor PD0325901 in 2D and 3D cell cultures.
Main Results:
- PD0325901 treatment increased GBM cell aggregate cohesion, stiffness, and viscosity, particularly with high fibronectin concentrations.
- Actin reorganization and increased focal adhesion kinase (FAK) localization at adhesion sites were observed.
- These changes led to enhanced substrate attachment, reduced cell motility, decreased dispersal velocity, and significantly inhibited 2D and 3D tumor growth.
Conclusions:
- Inhibition of the MAPK/ERK pathway via MEK inhibitors like PD0325901 shows promise for reducing glioblastoma cell dispersal.
- This therapeutic strategy may effectively decrease GBM growth and offers a potential avenue for treating recurrent disease.
