Experimental models and tools to tackle glioblastoma

Abstract

Glioblastoma multiforme (GBM) is one of the deadliest human cancers. Despite increasing knowledge of the genetic and epigenetic changes that underlie tumour initiation and growth, the prognosis for GBM patients remains dismal. Genome analysis has failed to lead to success in the clinic. Fresh approaches are needed that can stimulate new discoveries across all levels: cell-intrinsic mechanisms (transcriptional/epigenetic and metabolic), cell-cell signalling, niche and microenvironment, systemic signals, immune regulation, and tissue-level physical forces. GBMs are inherently extremely challenging: tumour detection occurs too late, and cells infiltrate widely, hiding in quiescent states behind the blood-brain barrier. The complexity of the brain tissue also provides varied and complex microenvironments that direct cancer cell fates. Phenotypic heterogeneity is therefore superimposed onto pervasive genetic heterogeneity. Despite this bleak outlook, there are reasons for optimism. A myriad of complementary, and increasingly sophisticated, experimental approaches can now be used across the research pipeline, from simple reductionist models devised to delineate molecular and cellular mechanisms, to complex animal models required for preclinical testing of new therapeutic approaches. No single model can cover the breadth of unresolved questions. This Review therefore aims to guide investigators in choosing the right model for their question. We also discuss the recent convergence of two key technologies: human stem cell and cancer stem cell culture, as well as CRISPR/Cas tools for precise genome manipulations. New functional genetic approaches in tailored models will likely fuel new discoveries, new target identification and new therapeutic strategies to tackle GBM.

Organoid Models of Glioblastoma to Study Brain Tumor Stem Cells

“…The emerging development of 3D organoids of GBM adds on to an abundance of choices to model this aggressive brain tumor (Robertson et al, 2019; Figure 1 and Table 1). It provides researchers with an additional tool to understand GBM biology, and predict tumor progression and response to treatment.…”

“…The best GBM model would be one that is complex enough to recapitulate features of the original tumor and simple enough to support investigation of different aspects of carcinogenesis in isolation. While the focus of this review is to look at emerging 3D in vitro models of GBM, several other approaches, including engineered mouse models or xenotransplantation, have been particularly useful to address tumor biology in other contexts [for a review of GBM models in vivo and in vitro, see Robertson et al (2019)]. Thus, researchers might have to balance pros and cons of the different models to find the best fit for their research question, and might have to combine more than one model to take advantage of their complementary strengths ( Table 1).…”

Gardenia jasminoides Enhances CDDP-Induced Apoptosis of Glioblastoma Cells via AKT/mTOR Pathway While Protecting Death of Astrocytes

“…Patient-derived primary GBM cell culture model or GBM organoid models, even an in vivo study should be carried out to validate the efficacy of GJ in GBM treatment. However, although its clinical application still requires intensive investigation, yet the subculture of the "classic" GBM cell lines such as U87MG allows researchers to investigate the characteristics of GBM without the interference of extrinsic variables [80]-thus, the first step of GBM research should be departed by GBM cell line experiments, and our study will provide evidence for a potentially effective and safer pharmaceutical agent for GBM treatment.…”

The CNS and the Brain Tumor Microenvironment: Implications for Glioblastoma Immunotherapy

“…This is due in part to their propagation and differentiation in cell cultures. Furthermore, these lines tend to harbor mutations that are not often associated with patient GBM lesions [ 92 ]. Instead, many now advocate for moving away from cultured cell lines towards patient-derived xenografts and organoids, as both retain mutations unique to the patient and also retain a sizable glioma stem cell pool.…”