Glioblastoma modeling with 3D organoids: progress and challenges

Abstract

Glioblastoma (GBM) is the most aggressive adult primary brain tumor with nearly universal treatment resistance and recurrence. The mainstay of therapy remains maximal safe surgical resection followed by concurrent radiation therapy and temozolomide chemotherapy. Despite intensive investigation, alternative treatment options, such as immunotherapy or targeted molecular therapy, have yielded limited success to achieve long-term remission. This difficulty is partly due to the lack of pre-clinical models that fully recapitulate the intratumoral and intertumoral heterogeneity of GBM and the complex tumor microenvironment. Recently, GBM 3D organoids originating from resected patient tumors, genetic manipulation of induced pluripotent stem cell (iPSC)-derived brain organoids and bio-printing or fusion with non-malignant tissues have emerged as novel culture systems to portray the biology of GBM. Here, we highlight several methodologies for generating GBM organoids and discuss insights gained using such organoid models compared to classic modeling approaches using cell lines and xenografts. We also outline limitations of current GBM 3D organoids, most notably the difficulty retaining the tumor microenvironment, and discuss current efforts for improvements. Finally, we propose potential applications of organoid models for a deeper mechanistic understanding of GBM and therapeutic development.

Keywords: 3-dimensional; brain tumor; glioblastoma; modeling; organoids.

Figure 1

GBM 3D organoids generated from either patient tissue or iPSC-derived brain organoids. Classification of methodologies to generate 3D GBM organoids (patient-derived versus iPSC-derived GBM organoids). Schematic illustration is included in the first column. Detailed methods are highlighted in the second column. Pros and cons of each method are highlighted in the last column.

Figure 2

Potential applications of GBM 3D organoids. GBM 3D organoids offer unique opportunities to study not only GBM biology including tumor progression, tumor migration, invasion and relapse, but also treatment responses with novel therapeutic methods such as immunotherapy and gene therapy. Further improvement of these models to mimic the complex tumor microenvironment is required to better recapitulate the tumor tissue and treatment response.