Considerations for modelling diffuse high-grade gliomas and developing clinically relevant therapies

Abstract

Diffuse high-grade gliomas contain some of the most dangerous human cancers that lack curative treatment options. The recent molecular stratification of gliomas by the World Health Organisation in 2021 is expected to improve outcomes for patients in neuro-oncology through the development of treatments targeted to specific tumour types. Despite this promise, research is hindered by the lack of preclinical modelling platforms capable of recapitulating the heterogeneity and cellular phenotypes of tumours residing in their native human brain microenvironment. The microenvironment provides cues to subsets of glioma cells that influence proliferation, survival, and gene expression, thus altering susceptibility to therapeutic intervention. As such, conventional in vitro cellular models poorly reflect the varied responses to chemotherapy and radiotherapy seen in these diverse cellular states that differ in transcriptional profile and differentiation status. In an effort to improve the relevance of traditional modelling platforms, recent attention has focused on human pluripotent stem cell-based and tissue engineering techniques, such as three-dimensional (3D) bioprinting and microfluidic devices. The proper application of these exciting new technologies with consideration of tumour heterogeneity and microenvironmental interactions holds potential to develop more applicable models and clinically relevant therapies. In doing so, we will have a better chance of translating preclinical research findings to patient populations, thereby addressing the current derisory oncology clinical trial success rate.

Organoids derived from metastatic cancers: Present and future

“…Compared with primary cancer organoids, metastatic cancer organoids also exhibit a greater growth rate and volume both in vitro and in vivo [ 62 , 63 , 65 ]. However, healthy epithelial organoids unexpectedly exhibit greater proliferation than organoids cultured from primary cancer, creating an interesting contradiction [ 83 ]. Further studies are needed to understand and reconcile the contrasting growth rates observed between normal epithelial cells, metastatic cells, and primary cancer cells, which may help to address the question of whether normal epithelial cells can replace cancer cells in organoid cultures.…”