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Acquired Temozolomide Resistance Instructs Patterns of Glioblastoma Behavior in Gelatin Hydrogels
Victoria A Kriuchkovskaia1,2, Ela K Eames1, Rebecca B Riggins3
1Department of Chemical & Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL, 61801, USA.
Abstract:
Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is a key factor contributing to abysmal prognosis, with less than 15 months median overall survival. Aggressive chemotherapy with the frontline therapeutic, temozolomide (TMZ), ultimately fails to kill residual highly invasive tumor cells after surgical resection and radiotherapy. Here, a 3D engineered model of acquired TMZ resistance is reported using two isogenically matched sets of GBM cell lines encapsulated in gelatin methacrylol hydrogels. Response of TMZ-resistant versus TMZ-sensitive GBM cell lines within the gelatin-based extracellular matrix platform is benchmarked and drug response at physiologically relevant TMZ concentrations is further validated. The changes in drug sensitivity, cell invasion, and matrix-remodeling cytokine production are shown as the result of acquired TMZ resistance. This platform lays the foundation for future investigations targeting key elements of the GBM tumor microenvironment to combat GBM's devastating impact by advancing the understanding of GBM progression and treatment response to guide the development of novel treatment strategies.
Insights
Glioblastoma (GBM) drug resistance limits treatment efficacy. A new 3D model using hydrogels effectively simulates acquired temozolomide (TMZ) resistance, revealing key changes in GBM cells and their microenvironment.
Area of Science:
- Oncology
- Biomaterials Science
- Cancer Biology
Background:
- Acquired drug resistance, particularly to temozolomide (TMZ), is a significant obstacle in glioblastoma (GBM) treatment, leading to poor patient outcomes.
- Current therapeutic strategies often fail against residual invasive GBM cells post-surgery and radiotherapy.
Purpose of the Study:
- To develop and validate a 3D engineered model that accurately recapitulates acquired TMZ resistance in GBM.
- To investigate the phenotypic and molecular changes associated with TMZ resistance in a physiologically relevant in vitro setting.
Main Methods:
- Utilized two isogenically matched sets of GBM cell lines (sensitive and resistant to TMZ).
- Encapsulated GBM cells within gelatin methacrylol hydrogels to create a 3D extracellular matrix model.
- Benchmarked the response of resistant versus sensitive GBM cells to TMZ at physiologically relevant concentrations.
Main Results:
- The 3D model successfully simulated acquired TMZ resistance in GBM.
- Demonstrated alterations in drug sensitivity, cell invasion capabilities, and the production of matrix-remodeling cytokines in TMZ-resistant GBM cells.
- Validated drug response at clinically relevant TMZ concentrations within the engineered model.
Conclusions:
- The developed 3D hydrogel model provides a robust platform for studying acquired TMZ resistance in GBM.
- This model facilitates a deeper understanding of GBM progression and treatment response by examining the tumor microenvironment.
- Lays the groundwork for developing novel therapeutic strategies targeting GBM's resistance mechanisms.
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