Abstract
BackgroundGlioblastoma is the most common and deadly form of primary brain cancer, accounting for more than 13,000 new diagnoses annually in the USA alone. Microglia are the innate immune cells within the central nervous system, acting as a front-line defense against injuries and inflammation via a process that involves transformation from a quiescent to an activated phenotype. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy.MethodsThis work used a brain-mimetic hydrogel system to study patient-derived glioblastoma specimens and their interactions with microglia. Here, glioblastoma cells were either cultured alone in 3D hydrogels or in co-culture with microglia in a manner that allowed secretome-based signaling but prevented direct GBM-microglia contact. Patterns of GBM cell invasion were quantified using a three-dimensional spheroid assay. Secretome and transcriptome (via RNAseq) were used to profile the consequences of GBM-microglia interactions.ResultsMicroglia displayed an activated phenotype as a result of GBM crosstalk. Three-dimensional migration patterns of patient-derived glioblastoma cells showed invasion was significantly decreased in response to microglia paracrine signaling. Potential molecular mechanisms underlying with this phenotype were identified from bioinformatic analysis of secretome and RNAseq data.ConclusionThe data demonstrate a tissue engineered hydrogel platform can be used to investigate crosstalk between immune cells of the tumor microenvironment related to GBM progression. Such multi-dimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.
Highlights
Glioblastoma (GBM) is the most common and deadly form of central nervous system cancer [1, 2]
Co-culture system assembly and mechanical testing of Gelatin methacrylate (GelMA) hydrogel We have previously developed a family of gelatin hydrogels to investigate pathophysiological processes underlying glioblastoma invasion and progression
This study describes a tissue engineering platform to examine the role of GBM-microglia crosstalk on processes associated with GBM progression
Summary
Glioblastoma (GBM) is the most common and deadly form of central nervous system cancer [1, 2]. The current standard of care for treating GBM consists of maximal surgical resection, radiotherapy, and concomitant and adjuvant chemotherapy with temozolomide [1, 3, 4] Despite this aggressive treatment strategy, GBM tumors commonly recur with a median survival of less than 18 months, and fewer than 5% of patients surviving to 5 years [5,6,7,8,9,10,11]. A central focus for improving GBM therapy is developing new tools to understand pathophysiological processes driving GBM invasion of the brain. Glioblastoma is the most common and deadly form of primary brain cancer, accounting for more than 13,000 new diagnoses annually in the USA alone. Crosstalk between GBM cells and microglia represents an important axis to consider in the development of tissue engineering platforms to examine pathophysiological processes underlying GBM progression and therapy
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