Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

Abstract

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.

Three-dimensional bioprinted glioblastoma microenvironments model cellular dependencies and immune interactions

“…HA is the most abundant ECM component in healthy brain tissue and promotes glioblastoma progression, including regulating glioblastoma invasion through the receptor for hyaluronan-mediated motility (RHAMM) and CD44, as well as other mechanical and topographical cues. 33 We used a physiologically relevant concentration of HA (0.25%) determined from clinical analysis of a diverse population of biopsy specimens from patients with different brain tumors. 34 While a range of molecular weight HAs are present in the brain, low molecular weight HA promotes GSC stemness and resistance.…”

“… 34 While a range of molecular weight HAs are present in the brain, low molecular weight HA promotes GSC stemness and resistance. 33 Thus, in this study, low molecular weight HA (200 kDa) was used to synthesize GMHA to model the pro-invasive brain tumor microenvironment. The mechanical properties of the model were characterized by the compressive modulus and pore sizes.…”

Organ-On-A-Chip in vitro Models of the Brain and the Blood-Brain Barrier and Their Value to Study the Microbiota-Gut-Brain Axis in Neurodegeneration

“…Despite these limitations, the integration of biomaterials and bioprinting in organs-on-a-chip modeling the brain and the BBB (and, more in general, in in vitro tissue models and disease models) would add complexity to recreate the microenvironment by mimicking the composition and anatomical properties of the ECM and providing key mechanical, biochemical and topographical cues as gradients or localized hotspots (Wolf et al, 2019). The relevance of these benefits has strongly emerged in research fields where the development of vascularized structures is of pivotal importance, like cancer research.…”

Designer Biomaterials to Model Cancer Cell Invasion In Vitro: Predictive Tools or Just Pretty Pictures?

“…HA is prevalent in the ECM throughout the body and is overexpressed in the tumor microenvironment of many cancers 22,23. HA is known to activate intracellular signaling pathways via cell surface receptors CD44 and the receptor for hyaluronan‐mediated motility (RHAMM), which are both known to drive invasion 24. In breast cancer, HA accumulation has been correlated with enhanced cancer cell invasiveness and poor patient outcomes,25 thereby making it a promising substrate to mimic the tumor microenvironment.…”

“…HA‐containing hydrogels have been used for in vitro studies of glioblastoma (GBM) invasion due to the prevalence of HA in the brain tumor microenvironment 24,27,28. Accordingly, Cha et al reported that the addition of HA to a collagen network resulted in increased invasion of patient‐derived glioblastoma cells 29.…”