Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens

Pedrón, Sara; Wolter, Gabrielle L.; Chen, Jee Wei E.; Laken, Sarah E.; Sarkaria, Jann N.; Harley, Brendan A.C.

doi:10.1016/j.biomaterials.2019.119371

Cited by 39 publications

(29 citation statements)

References 56 publications

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“…124 The effect of HA on resistance to erlotinib depends on the mutant status of EGFR, which can vary between patient-derived lines. 212 Thus, the incorporation of HA into engineered TME models has revealed key mechanisms by which HA drives GBM progression.…”

Section: Matrix Modelsmentioning

confidence: 99%

Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

et al. 2019

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Glioblastoma (GBM) is the most aggressive and common form of primary brain cancer. Several decades of research have provided great insight into GBM progression; however, the prognosis remains poor with a median patient survival time of ~ 15 months. The tumour microenvironment (TME) of GBM plays a crucial role in mediating tumour progression and thus is being explored as a therapeutic target. Progress in the development of treatments targeting the TME is currently limited by a lack of model systems that can accurately recreate the distinct extracellular matrix composition and anatomic features of the brain, such as the blood-brain barrier and axonal tracts. Biomaterials can be applied to develop synthetic models of the GBM TME to mimic physiological and pathophysiological features of the brain, including cellular and ECM composition, mechanical properties, and topography. In this Review, we summarize key features of the GBM microenvironment and discuss different strategies for the engineering of GBM TME models, including 2D and 3D models featuring chemical and mechanical gradients, interfaces and fluid flow. Finally, we highlight the potential of engineered TME models as platforms for mechanistic discovery and drug screening as well as preclinical testing and precision medicine.

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Section: Matrix Modelsmentioning

confidence: 99%

Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

et al. 2019

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“…b GBM39 invasion was significantly decreased due to co-culture with nMG (n = 6) compared to GBM39 alone (n = 3). **p < 0.01, ****p < 0.0001 GBM cell proliferation [52,78]. More, GBM-MG co-culture upregulated FOXO signaling, which has been linked to therapeutic resistance due to its contribution to DNA repair as well as mediation of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously developed a family of gelatin hydrogels to investigate pathophysiological processes underlying glioblastoma invasion and progression. Extensive biophysical performance data has previously been reported including network architecture and mechanical performance [52,53], water and small-molecule diffusivity [54][55][56], and the capacity to support growth and phenotypic studies of primary glioblastoma cells and cells from the neurovascular unit [57,58]. For this project, GBM and MG cells were maintained in three-dimensional culture in a 4 wt% methacrylamide-functionalized gelatin (GelMA) that exhibited a physiologically relevant Young's modulus (1.04 ± 0.10 kPa; n = 14; Fig.…”

Section: Co-culture System Assembly and Mechanical Testing Of Gelma Hmentioning

confidence: 99%

Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model

Chen

Lumibao

Leary

et al. 2020

J Neuroinflammation

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Background 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. 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. Methods This 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. Results Microglia 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. Conclusion The 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.

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“…KEGG analysis also showed strong upregulation in TH and STAT3 signaling, indicating that secreted factors from microglia may promote GBM proliferation, reduce apoptosis, and enhance chemotherapeutic resistance [64][65][66]. Recently, our group showed STAT3 is strongly activated in GBM, and inhibiting STAT3 can reduce GBM cell proliferation [67,68]. More, GBM-MG coculture upregulated FOXO signaling, which has been linked to therapeutic resistance due to its contribution to DNA repair as well as mediation of oxidative stress.…”

Section: Discussionmentioning

confidence: 84%

Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model

Chen

Lumibao

Leary

et al. 2020

Preprint

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BackgroundGlioblastoma is the most common and deadly form of primary brain cancer, accounting for more than thirteen thousand new diagnoses annually in the United States 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 multidimensional models may provide valuable insight to inform therapeutic innovations to improve GBM treatment.

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Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens

Cited by 39 publications

References 56 publications

Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model

Crosstalk between microglia and patient-derived glioblastoma cells inhibit invasion in a three-dimensional gelatin hydrogel model

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