Multicellular Model of Temozolomide Resistance in Glioblastoma Reveals Phenotypic Shifts in Drug Response and
Victoria A Kriuchkovskaia1,2, Ela K Eames1, Sydney A McKee2,3
1Dept. Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
Abstract:
Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, with limited survival outcomes due to tumor recurrence, mainly driven by GBM cell invasion and therapy resistance. Although temozolomide (TMZ) remains the standard-of-care chemotherapeutic, its long-term efficacy is often compromised by rapid emergence of acquired resistance, largely mediated by the DNA repair enzyme, methylguanine methyltransferase (MGMT). To investigate the interplay between tumor heterogeneity, drug resistance, and the extracellular matrix (ECM) microenvironment, we adapted a 3D methacrylamide-functionalized gelatin (GelMA) hydrogel model to study the behavior of mixed populations of TMZ-sensitive and TMZ-resistant GBM cells. Using both single-cell distributions and multicellular spheroids, we report the impact of heterogeneous cell populations and TMZ dosing regimens, including physiological, supraphysiological, and metronomic TMZ schedules, on drug response and migration. We show that the combination therapy of TMZ with an MGMT inhibitor, lomeguatrib, can modulate TMZ resistance in vitro. This hydrogel model enables systematic investigation of GBM heterogeneity, "go-or-grow" phenotypic plasticity, and therapeutic resistance in an ECM-rich microenvironment, offering a valuable platform for future translational research.
Insights
Glioblastoma (GBM) drug resistance can be modulated by combining temozolomide (TMZ) with an MGMT inhibitor. This 3D hydrogel model studies GBM heterogeneity and therapy resistance within the extracellular matrix.
Area of Science:
- Neuro-oncology
- Biomaterials Science
- Cancer Biology
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with poor outcomes due to recurrence driven by invasion and therapy resistance.
- Temozolomide (TMZ) is the standard chemotherapy, but acquired resistance, often mediated by MGMT, limits its long-term efficacy.
- Understanding GBM heterogeneity and the extracellular matrix (ECM) microenvironment is crucial for improving treatment.
Purpose of the Study:
- To investigate the interplay between GBM tumor heterogeneity, drug resistance, and the ECM microenvironment.
- To evaluate the impact of heterogeneous cell populations and various TMZ dosing regimens on drug response and migration.
- To assess the efficacy of combination therapy with TMZ and an MGMT inhibitor in a 3D GBM model.
Main Methods:
- Development of a 3D methacrylamide-functionalized gelatin (GelMA) hydrogel model.
- Culturing mixed populations of temozolomide-sensitive and -resistant GBM cells in single-cell and spheroid formats.
- Application of diverse TMZ dosing schedules (physiological, supraphysiological, metronomic) and combination therapy with an MGMT inhibitor (lomeguatrib).
Main Results:
- Demonstrated the impact of heterogeneous GBM cell populations and TMZ dosing on drug response and migration within the GelMA hydrogel.
- Showcased that combining TMZ with an MGMT inhibitor, lomeguatrib, can modulate temozolomide resistance in vitro.
- Validated the utility of the 3D hydrogel model for studying GBM behavior in an ECM-rich microenvironment.
Conclusions:
- The 3D GelMA hydrogel model effectively simulates GBM heterogeneity and ECM interactions.
- Combination therapy with TMZ and an MGMT inhibitor shows potential for overcoming drug resistance.
- This model provides a valuable platform for translational research in glioblastoma treatment strategies.
