Glioblastoma (Grade IV Astrocytoma;GBM) is a devastating cancer of the brain with median survival of 15 months, and 5% long-term survival. A key feature of GBM is its invasiveness: glioma cells spread from the primary tumor into the surrounding brain tissue by crawling through the brain micro-environment. If glioma cell crawling could be suppressed, it would potentially extend lifespan and increase the potential effectiveness for local and global therapeutic treatments. However, we do not adequately understand the mechanical and chemical basis of glioma migration in the brain. The goal of this project is to develop a mathematical/ computational model that will allow us to simulate glioma invasion on a computer, and, in the longer-term, perform virtual in silico drug screening. The model will have moderate complexity, with ~10-20 parameters, each representing a potential target for therapeutic intervention, either alone or in combination. To develop the model, we will start with an existing """"""""motor-clutch"""""""" model that includes both environmental mechanics and chemistry, and has been partially tested experimentally using neurons and glioma cells on compliant hydrogels.
In aim 1, the motor-clutch model will be further developed and tested on compliant hydrogels in vitro by interfering with motors and clutches, while also extending the stiffness range of the environment and testing cells obtained directly from the operating room.
In aim 2, the model will be tested in vivo by quantifying cell migration in live mouse brain slices as a function of cell adhesiveness, micromechanical brain stiffness, and brain micro-architecture.
In aim 3, engineered 2D and 3D microsystems will be fabricated to mimic the micro-confinement of brain tissue, which will provide more realistic in vitro systems intermediate in geometrical complexity between classic Petri dishes and animal models. To accomplish these aims requires building a highly interdisciplinary team with expertise in engineering, biology, and medicine. Overall, the project will establish the quantitative framework necessary to develop a model-driven approach to GBM, so that therapies can be designed and engineered with more predictable outcomes.

Public Health Relevance

This project will provide us with a computer simulator of brain cancer cell crawling, which will be used to identify and design new therapy options for an otherwise devastating disease known as glioblastoma. These options will specifically focus on disabling the cell's own crawling machinery.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Li, Jerry
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Biomedical Engineering
Schools of Engineering
United States
Zip Code
Ray, Arja; Morford, Rachel K; Ghaderi, Nima et al. (2018) Dynamics of 3D carcinoma cell invasion into aligned collagen. Integr Biol (Camb) 10:100-112
Prahl, Louis S; Bangasser, Patrick F; Stopfer, Lauren E et al. (2018) Microtubule-Based Control of Motor-Clutch System Mechanics in Glioma Cell Migration. Cell Rep 25:2591-2604.e8
Klank, Rebecca L; Decker Grunke, Stacy A; Bangasser, Benjamin L et al. (2017) Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level. Cell Rep 18:23-31
Mekhdjian, Armen H; Kai, FuiBoon; Rubashkin, Matthew G et al. (2017) Integrin-mediated traction force enhances paxillin molecular associations and adhesion dynamics that increase the invasiveness of tumor cells into a three-dimensional extracellular matrix. Mol Biol Cell 28:1467-1488
Bangasser, Benjamin L; Shamsan, Ghaidan A; Chan, Clarence E et al. (2017) Shifting the optimal stiffness for cell migration. Nat Commun 8:15313
Marko, Tracy A; Shamsan, Ghaidan A; Edwards, Elizabeth N et al. (2016) Slit-Robo GTPase-Activating Protein 2 as a metastasis suppressor in osteosarcoma. Sci Rep 6:39059
Venere, Monica; Horbinski, Craig; Crish, James F et al. (2015) The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma. Sci Transl Med 7:304ra143
Bangasser, Benjamin L; Rosenfeld, Steven S; Odde, David J (2013) Determinants of maximal force transmission in a motor-clutch model of cell traction in a compliant microenvironment. Biophys J 105:581-92
Bangasser, Benjamin L; Odde, David J (2013) Master equation-based analysis of a motor-clutch model for cell traction force. Cell Mol Bioeng 6:449-459