In Vitro Glioblastoma Models: A Journey into the Third Dimension

SIMPLE SUMMARY: In this review, the thorny issue of glioblastoma models is addressed, with a focus on 3D in vitro models. In the first part of the manuscript, glioblastoma features and classification are recapitulated, in order to highlight the major critical aspects that should be taken into account when choosing a glioblastoma 3D model. In the second part of the review, the 3D models described in the literature are critically discussed, considering the advantages, disadvantages, and feasibility for each experimental model, in the light of the potential issues that researchers want to address. ABSTRACT: Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults, with an average survival time of about one year from initial diagnosis. In the attempt to overcome the complexity and drawbacks associated with in vivo GBM models, together with the need of developing systems dedicated to screen new potential drugs, considerable efforts have been devoted to the implementation of reliable and affordable in vitro GBM models. Recent findings on GBM molecular features, revealing a high heterogeneity between GBM cells and also between other non-tumor cells belonging to the tumoral niche, have stressed the limitations of the classical 2D cell culture systems. Recently, several novel and innovative 3D cell cultures models for GBM have been proposed and implemented. In this review, we first describe the different populations and their functional role of GBM and niche non-tumor cells that could be used in 3D models. An overview of the current available 3D in vitro systems for modeling GBM, together with their major weaknesses and strengths, is presented. Lastly, we discuss the impact of groundbreaking technologies, such as bioprinting and multi-omics single cell analysis, on the future implementation of 3D in vitro GBM models.