Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics

Pedrón, Sara; Polishetty, H; Pritchard, Amanda M.; Mahadik, Bhushan; Sarkaria, Jann N.; Harley, Brendan A.C.

doi:10.1557/mrc.2017.85

Cited by 24 publications

(18 citation statements)

References 46 publications

(45 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our lab has developed methods to create spatially-graded hydrogels for the culture of patientderived GBM biospecimens and to examine therapeutic resistance to EGFR tyrosine kinase inhibitors [29,91], and could be adapted to generate spatially-graded perivascular models. The transition from GBM cell lines to patient-derived cells provides an opportunity to use this approach to study the behavior of cancer stem cells and their interactions with artificially created perivascular niches within a hydrogel environment.…”

Section: Gbm Progression Is Believed To Be Linked To the Interactionsmentioning

confidence: 99%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

View full text Add to dashboard Cite

Glioblastoma (GBM) is the most common primary malignant brain tumor, with patients exhibiting poor survival (median survival time: 15 months). Difficulties in treating GBM include not only the inability to resect the diffusively-invading tumor cells but also therapeutic resistance. The perivascular niche within the GBM tumor microenvironment contributes significantly to tumor cell invasion, cancer stem cell maintenance, and has been shown to protect tumor cells from radiation and chemotherapy. In this study, we describe the development of an in vitro artificial perivascular niche (PVN), culturing endothelial and stromal cells along with GBM cells within a methacrylamide-functionalized gelatin hydrogel, in order to examine howthe presence of the PVN alters global genomic expression profiles. Using RNA-seq, we demonstrate that the inclusion of perivascular niche cells with GBM cells upregulates genes related to angiogenesis and remodeling, while downregulated genes are related to cell cycle and DNA damage repair.Signaling pathways and genes commonly implicated in GBM malignancy, such as MGMT, EGFR, PI3K-Akt signaling, and Ras/MAPK signaling are also upregulated in the presence of perivascular niche cells. We describe the kinetics of gene expression within the PVN hydrogels over a course of 14 days, observing the patterns associated with previously-observed GBMmediated endothelial network co-option and regression that are altered in the presence of covalently-bound hyaluronic acid. We finally examine the effect of PVN culture on GBM cell responsiveness to temozolomide, a frontline chemotherapy used clinically against GBM.Notably, the presence of a PVN leads to significantly increased TMZ resistance compared to hydrogels containing only GBM cells. Overall, these results demonstrate that inclusion of cellular and matrix-associated elements of the PVN within in vitro models of GBM provide critical signals to regulate the phenotype and therapeutic responsiveness of GBM cells.

show abstract

Section: Gbm Progression Is Believed To Be Linked To the Interactionsmentioning

confidence: 99%

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Harley

Ngo

2018

Preprint

View full text Add to dashboard Cite

show abstract

“…To analyze the behavior of PDX cells, changes in gene expression and metabolism were measured. As a result, they showed that the therapeutic effect was influenced by HA concentration, cell type, and test group 48…”

Section: Microfluidic Devicementioning

confidence: 99%

Recent Strategies in Fabrication of Gradient Hydrogels for Tissue Engineering Applications

Yoon

Gajendiran

et al. 2019

Macromolecular Bioscience

View full text Add to dashboard Cite

Hydrogels are widely used as scaffold in tissue engineering field because of their ability to mimic the cellular microenvironment. However, mimicking a completely natural cellular environment is complicated due to the differences in various physical and chemical properties of cellular environments. Recently, gradient hydrogels provide excellent heterogeneous environment to mimic the different cellular microenvironments. To create hydrogels with an anisotropic distribution, gradient hydrogels have been widely developed by adopting several gradient generation techniques. Herein, the various gradient hydrogel fabrication techniques, including dual syringe pump systems, microfluidic device, photolithography, diffusion, and bio‐printing are summarized. As the effects of gradient 3D hydrogels with stems have been reviewed elsewhere, this review focuses principally on gradient hydrogel fabrication for multi‐model tissue regeneration. This review provides new insights into the key points for fabrication of gradient hydrogels for multi‐model tissue regeneration.

show abstract

“…We previously showed the significance of incorporating matrix-immobilized HA within gelatin hydrogels on GBM invasion capacity, [43] gene expression patterns [42] and the formation of robust endothelial cell networks as models of the tumor perivascular niche. [44] Therefore, we hypothesized that the presence of extracellular HA will affect the efficacy of cyclic erlotinib exposure.…”

Section: Erlotinib Inhibits Proliferation and Migration Of Egfr+ Gbm mentioning

confidence: 99%

“…[56] PDGFRα is the second most frequently amplified RTK in GBM behind EGFR, and their protein co-expression occurs in 37% of GBM. [42] Indeed, the lack of EGFR / PDGFRα co-expression in GBM tumors is related to reduced efficacy of TKIs. [23] We observed GBM6 vIII tumors express reduced levels of PDGFRα, regardless of matrix composition and number of doses ( Figure 5).…”

Section: Activation Of Compensatory Pathways: Erlotinib Promotes Uprementioning

confidence: 99%

“…In this context, the development of ex vivo tumor platforms can provide insight regarding acquired resistance as a function of matrix environment as well as drug dosage and scheduling in a reduced time scale. We have previously developed an in vitro 3D tumor model that recreates key features of the tumor environment, notably the presentation of brain-mimetic hyaluronic acid,[27,41] and we have shown that when used in combination with PDX, these hydrogels can offer a platform for profiling drug response [23,42]. The inclusion of hyaluronic acid does not significantly alter either hydrogel mechanical properties (EGelMA = 15.3 ± 2.1 and EGelMA/HAMA = 17.5 ± 1.1 kPa) or diffusion coefficient (DGelMA = 105.5 ± 7.1 and DGelMA/HAMA = 104.2 ± 7.3 µm…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Pedrón

Wolter

Chen

et al. 2019

Preprint

View full text Add to dashboard Cite

Therapeutic options to treat primary glioblastoma (GBM) tumors are scarce. GBM tumors with epidermal growth factor receptor (EGFR) mutations, in particular a constitutively active EGFRvIII mutant, have extremely poor clinical outcomes. GBM tumors with concurrent EGFR amplification and active phosphatase and tensin homolog (PTEN) are sensitive to the tyrosine kinase inhibitor erlotinib, but the effect is not durable. A persistent challenge to improved treatment is the poorly understood role of cellular, metabolic, and biophysical signals from the GBM tumor microenvironment on therapeutic efficacy and acquired resistance. The intractable nature of studying GBM cell in vivo motivates tissue engineering approaches to replicate aspects of the complex GBM tumor microenvironment. Here, we profile the effect of erlotinib on two patient-derived GBM specimens: EGFR+ GBM12 and EGFRvIII GBM6. We use a threedimensional gelatin hydrogel to present brain-mimetic hyaluronic acid (HA) and evaluate the coordinated influence of extracellular matrix signals and EGFR mutation status on GBM cell migration, survival and proliferation, as well as signaling pathway activation in response to cyclic erlotinib exposure. Comparable to results observed in vivo for xenograft tumors, erlotinib exposure is not cytotoxic for GBM6 EGFRvIII specimens. We also identify a role of extracellular HA (via CD44) in altering the effect of erlotinib in GBM EGFR+ cells by modifying STAT3 phosphorylation status. Taken together, we report an in vitro tissue engineered platform to monitor signaling associated with poor response to targeted inhibitors in GBM.

show abstract

Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics

Cited by 24 publications

References 46 publications

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Perivascular signals alter global gene expression profile of glioblastoma and response to temozolomide in a gelatin hydrogel

Recent Strategies in Fabrication of Gradient Hydrogels for Tissue Engineering Applications

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

Contact Info

Product

Resources

About