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 intra- 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.

Brain-wide neuronal circuit connectome of human glioblastoma

“…This strategy has been widely employed to elucidate whole-brain neuronal networks with specific neurons 22,23 or oligodendrocyte precursor cells 24 as starter cells. Here we performed in vivo retrograde monosynaptic rabies virus tracing of transplanted patient-derived GBM organoids (GBOs) 25,26 to characterize the landscape of neuronal innervation onto GBM cells and further investigated functional effects of neuromodulatory inputs onto GBM cells.…”