Authors:

Gloria Yao

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About Paper:

spheroid cultures of glioblastoma cells in collagen matrices can be used to mimic the in vivo environment of tumors in the human brain. Agent-based biophysical modeling can also be used to simulate glioblastoma spheroid growth under clinical conditions to better understand the detailed biophysical and molecular mechanisms of spheroid expansion and invasion. Brownian Dynamics Tumor Simulator (BDTS) utilizes volume exclusion and off-lattice stochastic migration to improve the realism of tumor progression models. Unlike traditional reaction-diffusion (RD) models that treat cells as point particles and allow unphysical overlap, BDTS preserves the finite size of individual cells and enforces non-overlapping constraints, generating spatial dynamics such as crowding-induced jamming and edge-biased proliferation to more accurately reflect real tumor behavior. This study investigates the hypothesis that BDTS can accurately reproduce drug-induced suppression of proliferation and migration in U-251 green florescent protein (GFP)-labeled glioblastoma spheroids, thereby utilizing single-cell behavior and bulk tumor expansion to inform rational design of therapeutic strategies. Spheroids are cultured from U-251-GFP glioblastoma cell lines in basement membrane matrix, plated into collagen, treated with temozolomide (TMZ) as chemotherapeutic treatment or dimethyl sulfide (DMSO) as control, then imaged over time using epi-fluorescence microscopy. A BDTS model is fitted to the experimental data using biological mechanisms of random motility, cell growth, mitotic division, and a Brownian random walk to model the dynamics of glioblastoma spheroid growth under DMSO and TMZ conditions. Parameters are initially tuned based on literature values, then iteratively fitted to the area- over-time curve of the in vitro experiments. Both experimental and simulated images are fed through a Fiji and MATLAB analysis pipeline for segmentation and quantification. The TMZ-treated spheroids grow at slower rates and exhibit more compact GFP intensity profiles compared to the control, indicative of limited outward migration and consistent with reduced proliferation the presence of chemotherapeutic drugs. The simulated TMZ spheroids yield parameters with slower doubling time, lower diffusion, and greater variability in gene expression compared to the DMSO. These trends align with expected biological responses to TMZ as a tumor suppression alkylating agent. Both the experimental in vitro and Brownian dynamics spheroid models effectively recapitulate the behavioral responses of glioblastoma under different treatments. BDTS proves promising for the modeling and examination of glioblastoma tumor cells and chemotherapy mechanisms.

Source:

Brown / SPRINT|Undergraduate Teaching and Research Awards (UTRA)

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Co-authors:

Gloria Yao